Podcasts about tmb

Tonight on TMB, we'll have a long time friend of the program William Russell on the show. Bill as we know him has been a fixture in grass roots racing forever. He's a trackday guy, club racer, has raced nationals, crewed for riders doing the nationals, coached people etc.. I'm sure this will be a fun chat. Check him out on IG: @motofreak46Get signed up for your next TrackDaz event:http://trackdaz.trackrabbit.comYamaha OEM Oil Filter:https://amzn.to/3CBwpJqFire-Power Full Synth 10W-40https://amzn.to/4hVu23YThe above are Amazon affiliate links.. this means if you click to purchase, we make a commish at no additional cost to you. -thanks for your support **Want a deal on some boxo tools? Use the following link, and save 10% while also helping us get a bit of a commish! Its Win-Win!https://boxousa.com/TrackDazOr the code TrackDaz10**buy some celcuis drinks!https://amzn.to/3UVITBF**ROCKWELL WATCHES: Check out their website https://rockwelltime.com/Enter the code "TDZ20" at checkout and save 20% on a new Rockwell!!Sign up for your next TrackDaz event here: http://www.trackdaz.com*PIRELLI TIRES!! **You can get your Pirelli rubber from us directly on our registration site. Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdazFollow the TrackDaz Crew:@chili144@jimmyz853@phen2210@gil823@formula_r@chili144@lgbrown_@dkm60@canea121@g_offsims@ricardo.abueg@trackdazkaren@fharo3@modbaez@m39023@dreek46@bubblesrides @r6_krissy_@shaunsummers62

A solo episode to conclude our Ballet Teaching series — discussing why great ballet teaching begins with who you are, how you grow, and the courage to keep evolving. _____ Join the Balanced Ballerinas EXCLUSIVE Teachers Facebook Group here: https://www.facebook.com/groups/balancedballerinasteachers My Instagram! @thebalancedballerina Community Instagram! @balancedballerinas Facebook - Balanced Ballerinas And join the SECRET Facebook group here: https://www.facebook.com/groups/balancedballerinas/ Join the Balanced Ballerinas FREE 5 Day Challenge here: www.balancedballerinas.com/challenge Prenatal, healing or beginner ballet student? This course was designed for you: https://www.balancedballerinas.com/butterballet My Signature 12 Week Adult Ballet Course: https://www.balancedballerinas.com/12weekadultballetcourse The Marketing Blueprint For Dance Teachers & Studio Owners: https://www.balancedballerinas.com/TMB

Continuing our mini-series The Art & Impact of Ballet Teaching, I'm joined by someone who has long inspired me with her grace, wisdom, and deep love of the art form—Jane Inglis-Keen. ___ Join the Balanced Ballerinas EXCLUSIVE Teachers Facebook Group here: https://www.facebook.com/groups/balancedballerinasteachers My Instagram! @thebalancedballerina Community Instagram! @balancedballerinas Facebook - Balanced Ballerinas And join the SECRET Facebook group here: https://www.facebook.com/groups/balancedballerinas/ Join the Balanced Ballerinas FREE 5 Day Challenge here: www.balancedballerinas.com/challenge Prenatal, healing or beginner ballet student? This course was designed for you: https://www.balancedballerinas.com/butterballet My Signature 12 Week Adult Ballet Course: https://www.balancedballerinas.com/12weekadultballetcourse The Marketing Blueprint For Dance Teachers & Studio Owners: https://www.balancedballerinas.com/TMB

In today's episode of Backpacker Radio, presented by The Trek, brought to you by Topo Athletic, we are joined by Jamie Lambert. We learn why Jamie doesn't have a trail name, and why it's definitely not Strap On, what it's like to thru-hike with your sister- which she did on the PCT in 2018, what it is about thru-hiking that makes it so addictive for her- having taken on long hikes every year over the last 8 seasons, what it's like to become social media famous, and much more. We wrap the show with an overview from day one of Trail Days, some new legislation that could result in finally completing the CDT, why a section of the PCT has been closed for MYLFs, our BS TED talks, and the triple crown of words we'll never pronounce correctly. Topo Athletic: Use code “TREKSPRING15” at topoathletic.com. Gossamer Gear: Use code “BACKPACKER20” for 20% off packs at gossamergear.com.  Ombraz: Use code “BACKPACKER30” for $30 off at ombraz.com/discount/backpacker30. Betterment: Learn more at betterment.com/trek. [divider] Interview with Jamie Lambert Jamie's Instagram Time stamps & Questions 00:05:00 - Trail Days Day 1 Recap 00:11:00 - Introducing Jamie 00:14:00 - How did you decide to hike the PCT with your sister? 00:18:45 - What's it like working for an orthodontist? 00:23:18 - What was it like to hike with your sister? 00:30:00 - Discussion about the Colorado Trail 00:35:08 - What is it about thru-hiking that you love? 00:37:45 - Have you hit a fork in the road feeling about thru-hiking? 00:41:10 - If you had to settle somewhere, where would you choose? 00:45:15 - What's the brief overview of the Tour du Mont Blanc? 00:47:15 - Why do people hike counter clockwise? 00:51:20 - Discussion about lodging and towns along the TMB 00:53:00 - Are there places along the trail where you could stay a few days? 00:55:10 - Discussion about guiding services on the TMB 00:56:51 - What time of year would you recommend? 01:00:30 - What changes in items did you carry? 01:01:45 - When did you know you wanted to hike the CDT too? 01:05:22 - Discussion about hiking the AT third 01:08:40 - How do you handle people fangirling around you? 01:11:02 - What's been the highlight of the AT for you so far? 01:12:05 - What's the most embarrassing thing that's happened to you while hiking? 01:14:05 - What's the scariest thing that's happened to you while hiking? 01:18:00 - Do you have any advice for solo female backpackers? 01:22:25 - What's your biggest beginner blunder? 01:24:44 - What do your resupplies look like these days? 01:30:00 - What shoes are you using? 01:33:30 - Peak Performance Question: What is your top performance enhancing or backpacking hack? 01:35:25 - Reminders: Take our survey! Listen to our episodes ad-free on Patreon and apply to blog for the Trek! Segments Trek Propaganda:  47 Years Later, the CDT Still Isn't Complete — New Legislation in Congress Aims To Change That by Katie Jackson This Section of the PCT Has Been Closed for 20 Years. The Reason? MYLFs by Kelsey Nannini QOTD:  If you had to give a TED Talk on something you're not a real expert on—but could fake it—what topic would you choose? Triple Crown of words you'll never pronounce correctly Mail Bag 5 Star Review [divider] Check out our sound guy @my_boy_pauly/ and his coffee. Sign up for the Trek's newsletter Leave us a voicemail! Subscribe to this podcast on iTunes (and please leave us a review)!  Find us on Spotify, Stitcher, and Google Play. Support us on Patreon to get bonus content. Advertise on Backpacker Radio Follow The Trek, Chaunce, Badger, and Trail Correspondents on Instagram. Follow Backpacker Radio, The Trek and Chaunce on YouTube. Follow Backpacker Radio on Tik Tok.  Our theme song is Walking Slow by Animal Years. A super big thank you to our Chuck Norris Award winner(s) from Patreon: Alex and Misty with NavigatorsCrafting, Alex Kindle, Andrew, Austen McDaniel, Brad & Blair Thirteen Adventures, Brent Stenberg, Bryan Alsop, Carl Houde, Christopher Marshburn, Coach from Marion Outdoors, Eric Casper, Erik Hofmann, Ethan Harwell, Gillian Daniels, Greg Knight, Greg Martin, Greg McDaniel may he bring honor to his name, Griffin Haywood, Hailey Buckingham, Lauren F, Patrick Cianciolo, Rebecca Brave, Sawyer Products, SPAM, Timothy Hahn, Tracy ‘Trigger' Fawns A big thank you to our Cinnamon Connection Champions from Patreon: Bells, Benjy Lowry, Bonnie Ackerman, Brett Vandiver, Chris Pyle, David, David Neal, Dcnerdlet, Emily Galusha, Greg Floravanti “Lumberjack”, Jack Greene, Jeanie, Jeanne Latshaw, Luke Netjes, Merle Watkins, Peter, Ruth S, and Spencer Hinson.

For episode 227 of our award-winning podcast⁠, we are celebrating our forty-third anniversary.On this date in 1982, we found ourselves kneeling at the altar in old St. Teresa's of Avila Catholic Church on West King Street in Carson City, Nevada. In the days since, we had a bunch of kids, saw the Information Age revolution, watched our country transform, and grew together as a couple. Sometime in there, we started our little publishing company Two Moore Books, LLC, and we published fifteen books.It's been a ride.As part of the TMB experience, we have writers from Nevada and across the country coming onto our little podcast. This schedule is tentative and (hello, redundancy) subject to change:June 8: Interview - Kendall BrownJune 11: Interview - Teresa Breeden (Nevada Author Network)June 15: Our regular podcastJune 18: Interview - Sue Dugan (Nevada Author Network)June 22: Interview - Rich MorenoJune 25: Suzanne Morgan (Nevada Author Network)June 29: Interview - Our regular podcastYou can meet and greet us at these two great book signings:-Barnes and Noble in south Reno on Saturday, June 28, 2025 at 1:00pm.-Artown at the Reno Public Market (Virginia and Plumb) on Saturday, July 5, 2025 at 1:00pm.Thank you for joining us on the big 43rd anniversary. TIA LYL!⁠please buy us coffee!⁠For those who listen on the way to work, we are on these fine podcast platforms: ⁠Spotify⁠ ⁠Apple⁠ ⁠Pocket Casts⁠ ⁠Radio Public⁠Note: Two Moore Books, LLC does not receive financial compensation for promoting third-party businesses and websites. We are speaking to our specific experiences. Your mileage may vary.

This week on The Balanced Ballerinas Podcast, I'm honoured to share a conversation with the legendary Lynne Charles as we launch our new mini-series, The Art & Impact of Ballet Teaching. Lynne's career is nothing short of extraordinary—dancing with American Ballet Theatre, London Festival Ballet, and as a principal with Hamburg Ballet and Deutsche Oper Ballet. But it's the teacher she's become that truly inspired this episode. _____ Join the Balanced Ballerinas EXCLUSIVE Teachers Facebook Group here: https://www.facebook.com/groups/balancedballerinasteachers My Instagram! @thebalancedballerina Community Instagram! @balancedballerinas Facebook - Balanced Ballerinas And join the SECRET Facebook group here: https://www.facebook.com/groups/balancedballerinas/ Join the Balanced Ballerinas FREE 5 Day Challenge here: www.balancedballerinas.com/challenge Prenatal, healing or beginner ballet student? This course was designed for you: https://www.balancedballerinas.com/butterballet My Signature 12 Week Adult Ballet Course: https://www.balancedballerinas.com/12weekadultballetcourse The Marketing Blueprint For Dance Teachers & Studio Owners: https://www.balancedballerinas.com/TMB

Los portavoces de los grupos con representación en el Parlamento de Bizkaia se sientan hoy ante los micrófonos de Radio Bilbao para debatir sobre algunos de los temas clave de la actualidad foral. Analizamos la sanción a la planta TMB de Arraiz por riesgos laborales, el avance del cable eléctrico entre Gatika y Burdeos, la nueva ordenanza de aparcamiento en Lekeitio tras la anulación judicial del decreto anterior, y la renuncia de la Diputación al proyecto del tren lanzadera entre Sestao y Areeta 

In this JCO Precision Oncology Article Insights episode, Jiasen He summarizes "Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma” by Dr. Miles C. Andrews, et al. published on June 07, 2024. Transcript The guest on this podcast episode has no disclosures to declare. Jiasen He: Hello and welcome to the JCO Precision Oncology Article Insights. I'm your host, Jiasen, and today we'll be discussing the JCO Precision Oncology article, "Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma," by Dr. Miles C. Andrews and colleagues. This study was supported by Foundation Medicine, a for-profit company that conducts FDA-regulated molecular diagnostics, including assays used to measure tumor mutational burdens, or TMB, as described in this article. Immune checkpoint inhibitor (ICI) therapy has become a cornerstone in the treatment of metastatic melanoma. They work by activating the patient's own immune system, representing a fundamentally different approach from traditional chemotherapy. Several biomarkers have emerged as promising tools to predict ICI therapy response, and TMB is one of the most extensively studied. TMB is defined as the number of somatic mutations per megabase of an interrogated genome sequence. In the KEYNOTE-158 study, patients with high TMB showed better response rates and longer progression-free survival compared to those with low TMB, which led to the FDA tumor-agnostic approval of TMB as a biomarker to guide ICI therapy. In this manuscript, Dr. Andrews and colleagues set out to answer an important question: does TMB predict outcomes of ICI therapy in real-world patients with advanced melanoma? To explore this, they analyzed de-identified data from the nationwide Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). To be included, patients needed to have had at least two visits to a Flatiron Health clinic and a Foundation Medicine Comprehensive Genomic Profiling report. Eligible patients had received first-line treatment with either monotherapy (nivolumab or pembrolizumab) or dual therapy with the combination of ipilimumab and nivolumab for metastatic melanoma. They also needed a tissue-based TMB score from either the FoundationOne or FoundationOne CDx genomic test. For this study, TMB less than 10 mutations per megabase was considered low TMB; TMB equal to or more than 10 mutations per megabase was considered high TMB; and TMB equal to or more than 20 mutations per megabase was considered very high TMB. Of the 497 patients in the final cohort, 29% had low TMB, while 71% had high TMB, and 50% had very high TMB. The authors observed that patients with very high TMB were more often male, had BRAF wild-type tumors, and were more likely to receive anti-PD-1 monotherapy. This group also had tumors more commonly sampled from brain and lung metastases. Patients with high TMB but not very high TMB were more likely to carry the BRAF V600K mutation and were least likely to have lung metastases. Meanwhile, those with low TMB tended to be younger and had disease limited to non-visceral sites. As expected, the presence of ultraviolet mutation signatures, a known driver of melanoma, was strongly associated with TMB. UV signatures were found in just 18% of the low TMB group, but in 89% of the high TMB and 93% of the very high TMB group. High TMB was found to be prognostic of improved real-world progression-free survival (PFS) and overall survival (OS) in patients receiving both monotherapy and dual immune checkpoint inhibitors, even after adjusting for other established prognostic factors. Interestingly, in the low TMB group, overall survival was likely confounded by the availability of effective second-line targeted therapy, particularly for BRAF-mutant patients. These patients had better outcomes compared to their BRAF wild-type counterparts, likely reflecting a greater reliance on salvage therapy in low TMB patients who derived less benefit from first-line immunotherapy. The authors then further examined the ICI outcomes using stepwise TMB thresholds, with TMB less than 10 as low, 10 to 19 as high, and equal to or more than 20 as very high. For those receiving ICI monotherapy, both PFS and OS were highest in the very high TMB group, followed by the high TMB group, and lowest in the low TMB group. However, in patients treated with dual ICI therapy, the results diverged. While low TMB patients still had the poorest outcomes, those with high TMB (mutations 10 to 19 per megabase) had better PFS and overall survival than those with very high TMB (mutations equal to or more than 20 per megabase). The authors then conducted exploratory multivariable modeling, showing that among very high TMB patients with BRAF mutations, dual ICI therapy was associated with a significantly higher hazard ratio compared to monotherapy. They concluded that dual ICI may not benefit, and could even harm, patients with very high TMB, whereas those with TMB between 10 and 20 mutations per megabase may get more from the intensified regimen. Importantly, as the authors stated in the manuscript, we need to note that in this cohort, very high TMB patients were more likely to have brain metastases at treatment initiation, be male, and lack BRAF V600E/K mutations—all factors associated with poorer prognosis. This might partially explain inferior outcomes to dual ICI in very high TMB patients, as patients were not randomly assigned to therapy in this retrospective, real-world study. As such, these findings should be interpreted with caution and validated in future studies. In summary, this study showed that in a real-world setting, high tumor mutational burden predicts better outcomes with immune checkpoint inhibitor therapy in patients with advanced melanoma. Interestingly, the authors found that dual ICI therapy may offer no added benefit for patients with very high TMB compared to ICI monotherapy. However, this was a retrospective, non-randomized study, and the cohorts were imbalanced for some known risk factors, which could confound outcomes. As a result, these findings should be interpreted with caution and will need to be validated in future prospective studies. Thank you for tuning into JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. Until then, stay informed and stay inspired. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

This week the TMB crew throw open the door and invite you all in as they discuss the viral vampire epic, Sinners (2025). They sink their teeth into this modern classic, headlined by the hip (Michael B Jordan)² and directed by the cool Coogler. Join in as they breakdown and banter about the blues, booze and blood in this blockbuster! 

On the TMB show, I have all sorts of personalities on. From Club to Pro, and just about everything between, I'm interested in talking to riders, team owners, crew members, etc.. This one is a club racer out of Minnesota. He races with the original CRA. I'm looking forward to sharing his stories and perspectives. Should be fun.Get signed up for your next TrackDaz event:http://trackdaz.trackrabbit.comYamaha OEM Oil Filter:https://amzn.to/3CBwpJqFire-Power Full Synth 10W-40https://amzn.to/4hVu23YThe above are Amazon affiliate links.. this means if you click to purchase, we make a commish at no additional cost to you. -thanks for your support **Want a deal on some boxo tools? Use the following link, and save 10% while also helping us get a bit of a commish! Its Win-Win!https://boxousa.com/TrackDazOr the code TrackDaz10**buy some celcuis drinks!https://amzn.to/3UVITBF**ROCKWELL WATCHES: Check out their website https://rockwelltime.com/Enter the code "TDZ20" at checkout and save 20% on a new Rockwell!!Sign up for your next TrackDaz event here: http://www.trackdaz.com*PIRELLI TIRES!! **You can get your Pirelli rubber from us directly on our registration site. Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdazFollow the TrackDaz Crew:@chili144@jimmyz853@phen2210@gil823@formula_r@chili144@lgbrown_@dkm60@canea121@g_offsims@ricardo.abueg@trackdazkaren@fharo3@modbaez@m39023@dreek46@bubblesrides @r6_krissy_@shaunsummers62

In this episode expert guest Dr. CM Schade elaborates on the Texas Medical Board's revamped CME requirements for opioid prescriptions, which now focus only on direct patient care physicians. He offers insights into how the new rules bring flexibility while placing an emphasis on meticulous documentation. With decades of experience in legislative advocacy, Dr. Schade shares valuable tips on navigating these changes and encourages utilizing TMA's educational resources. Access the ondemand webinar - Prescribing and Monitoring of Controlled Substances Access current TMB rules

Learn more about Cindy's incredible work here: https://www.classfortheheart.com/ ____ Join the Balanced Ballerinas EXCLUSIVE Teachers Facebook Group here: https://www.facebook.com/groups/balancedballerinasteachers My Instagram! @thebalancedballerina Community Instagram! @balancedballerinas Facebook - Balanced Ballerinas And join the SECRET Facebook group here: https://www.facebook.com/groups/balancedballerinas/ Join the Balanced Ballerinas FREE 5 Day Challenge here: www.balancedballerinas.com/challenge Prenatal, healing or beginner ballet student? This course was designed for you: https://www.balancedballerinas.com/butterballet My Signature 12 Week Adult Ballet Course: https://www.balancedballerinas.com/12weekadultballetcourse The Marketing Blueprint For Dance Teachers & Studio Owners: https://www.balancedballerinas.com/TMB

You can find more of Dr Nya's important work at her website here: https://www.1nyama.com/ You can purchase 'Skin Colored Pointes' on Amazon here: https://www.amazon.com/Skin-Colored-Pointes-Interviews-Ballet/dp/1476687056 ________ Join the Balanced Ballerinas EXCLUSIVE Teachers Facebook Group here: https://www.facebook.com/groups/balancedballerinasteachers My Instagram! @thebalancedballerina Community Instagram! @balancedballerinas Facebook - Balanced Ballerinas And join the SECRET Facebook group here: https://www.facebook.com/groups/balancedballerinas/ Join the Balanced Ballerinas FREE 5 Day Challenge here: www.balancedballerinas.com/challenge Prenatal, healing or beginner ballet student? This course was designed for you: https://www.balancedballerinas.com/butterballet My Signature 12 Week Adult Ballet Course: https://www.balancedballerinas.com/12weekadultballetcourse The Marketing Blueprint For Dance Teachers & Studio Owners: https://www.balancedballerinas.com/TMB

Join the Balanced Ballerinas EXCLUSIVE Teachers Facebook Group here: https://www.facebook.com/groups/balancedballerinasteachers My Instagram! @thebalancedballerina Community Instagram! @balancedballerinas Facebook - Balanced Ballerinas And join the SECRET Facebook group here: https://www.facebook.com/groups/balancedballerinas/ Join the Balanced Ballerinas FREE 5 Day Challenge here: www.balancedballerinas.com/challenge Prenatal, healing or beginner ballet student? This course was designed for you: https://www.balancedballerinas.com/butterballet My Signature 12 Week Adult Ballet Course: https://www.balancedballerinas.com/12weekadultballetcourse The Marketing Blueprint For Dance Teachers & Studio Owners: https://www.balancedballerinas.com/TMB

Talkin' Motorbikes with Kevin "Kevdawg" Rodio, the team owner of Rodio Racing. This is the second time Kev has been on TMB. Since getting the Twins Cup Championship in MotoAmerica, what has he and his team been up to? What are the plans? Is Kevin moving the team over to Supersport class? What's the deal with the marketplace trolling?? Oh and most importantly Did they get the hummer fixed? -LOL Get signed up for your next TrackDaz event:http://trackdaz.trackrabbit.comYamaha OEM Oil Filter:https://amzn.to/3CBwpJqFire-Power Full Synth 10W-40https://amzn.to/4hVu23YThe above are Amazon affiliate links.. this means if you click to purchase, we make a commish at no additional cost to you. -thanks for your support **Want a deal on some boxo tools? Use the following link, and save 10% while also helping us get a bit of a commish! Its Win-Win!https://boxousa.com/TrackDazOr the code TrackDaz10**buy some celcuis drinks!https://amzn.to/3UVITBF**ROCKWELL WATCHES: Check out their website https://rockwelltime.com/Enter the code "TDZ20" at checkout and save 20% on a new Rockwell!!Sign up for your next TrackDaz event here: http://www.trackdaz.com*PIRELLI TIRES!! **You can get your Pirelli rubber from us directly on our registration site. Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdazFollow the TrackDaz Crew:@chili144@jimmyz853@phen2210@gil823@formula_r@chili144@lgbrown_@dkm60@canea121@g_offsims@ricardo.abueg@trackdazkaren@fharo3@modbaez@m39023@dreek46@bubblesrides @r6_krissy_@shaunsummers62

Chris shares his eyepiece plans for the 7” TMB refractor and the guys continue the conversation on cleaning eyepieces. 

This one should be fun. a TMB epsiode with my longtime racing homie, Berto Wooldridge, to reminisce about our early days as Novices at Willow Springs and dive deep into his decades of experience in the club racing world. Berto has been a fixture in the AFM (American Federation of Motorcyclists) for years, even serving as president, and along the way, Trust me, this dude has stories!

JCO PO author Dr. David R. Gandara at UC Davis Comprehensive Cancer Center, shares insights into his JCO PO article, “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer,” one of the Top Articles of 2024. Host Dr. Rafeh Naqash and Dr. Gandara discuss how the PROphet® blood test supports first-line immunotherapy treatment decisions for metastatic NSCLC patients. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today, we are absolutely thrilled to be joined by Dr. David R. Gandara, Professor of Medicine Emeritus, Co-Director of the Center for Experimental Therapeutics and Cancer and Senior Advisor to the Director at UC Davis Comprehensive Cancer Center and also the senior author of the JCO Precision Oncology article entitled “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer.” This was one of the top performing articles of 2024, which is one of the reasons why we wanted to bring it in for a podcast discussion. At the time of this recording, our guest's disclosures will be linked in the transcript.  David, it is an absolute pleasure to have you today. For somebody like you who's led the field of lung cancer over the years, I'm really excited that you are going to be talking to us about this very interesting article, especially given that I think you're one of the big proponents of liquid biopsies and plasma-based testing. So, for the sake of our listeners - which comprises of academic oncologists, community oncologists, trainees - could you tell us where the biomarker landscape for non-small cell lung cancer is currently, and then we can try to take a deeper dive into this article. Dr. David Gandar: Okay. Well, thank you, Rafeh. It's a pleasure to be with you here today. And I think the current landscape for biomarkers for immunotherapy in non-small cell lung cancer is a mess. There's no better way to describe it. That makes this paper describing a new plasma proteomic assay even more important. So I'll just give you a perspective. There are 14 trials, phase three trials, that were done in first line non-small cell lung cancer advanced stage of immunotherapy versus chemotherapy and some other aspects, although they vary tremendously. Some of them were checkpoint monotherapy, some combined with chemotherapy, some combined with CTLA-4 inhibitors and so forth. 12 out of the 14 were positive, 12 got FDA approval. So there are 12 different options that an oncologist could use. Some of them were squamous cell only, some non-squamous, some used PD-L1 as a biomarker driven part of the study. Some used TMB, tumor mutational burden, some were agnostic. So when you put all of this together, an oncologist can pick and choose among all these various regimens. And by and large, it's PD-L1 that is the therapeutic decision maker.  ASCO actually, I think, has done the very best job of making a guideline, and it's, as you well know, called a living guideline, it's dynamic. And it is much easier to interpret, for me and I think for oncologists, than some of the other guidelines. It's got a green light and a red light, it may be kind of orange. And so the green light means this is a strong recommendation by the guideline committee. The orange means it's weak. For this purpose, non-small cell lung cancer, advanced stage, only a very few of the recommendations were green. It's mainly monotherapy and patients with cancers with a PD-L1 over 50%. In our surveys, at our meetings, less than 50% of oncologists in the United States are following these guidelines. Why? Because they don't trust the biomarker. And TMB has the same sort of limitations. They're not bad biomarkers, they're incomplete. They're only looking at a part of the story. So that means we need a new biomarker. And this is one that, I think, the data are quite impressive and we'll discuss it more. Dr. Rafeh Naqash: Absolutely. Like you said, abundance of many therapy options, but not necessarily everything works the same in different subsets of PD-L1 positivity or different subsets of patients with different levels of tumor burden. And like you said, again, difficulty in trying to identify the right biomarker. And that's a nice segue to this PROphet test that you guys ran. So can you tell us a little bit about the plasma proteomic assay? Because to the best of my knowledge, there's not a lot of validated plasma proteomic assays. A lot has been done on the tumor tissue side as far as biomarkers are concerned, but not much on the blood side, except for maybe ctDNA MRD testing. So what was the background for trying to develop a plasma-based proteomic test? And then how did this idea of testing it in the lung cancer setting come into play? And then we can go into the patient population specifics, the cohort that you guys have. Dr. David Gandara: Okay. Well, of course there's a company behind this assay, it's called OncoHost, and I'm a consultant for them. And they came to me two years ago and they said, “We have something different from anyone else.” And they explained the science to me, as well as some other lung cancer experts here in the United States. I'm not a proteomic expert, of course, but they developed an AI machine learning platform to assess plasma proteins in normal people and in people with cancer, and specifically then in people with non-small cell lung cancer. They identified over 7,000 proteins that had cancer implications for therapy, for resistance, for prognosis, etc., and they categorized them based on the literature, TCGA data, etc., and used this machine learning process to figure out which proteins might be most specific for non-small cell lung cancer. And that's where they started. And so out of that 7,000 proteins, where they've identified which ones are angiogenic, which ones are involved with EMT or cell cycle or whatever it might be, they distilled it down to 388 proteins which they thought were worth testing in non-small cell lung cancer. And that's when I became involved.  They had a retrospective cohort of patients that had been treated with various immunotherapies. They looked at the analytic validation first, then applied it to this cohort. It looked good. Then they had a very large cohort, which they split, as you usually do with an assay, into a test set and then a validation set. For the test set, they wanted something more than a response. They wanted some indicator of long term benefit because that's where immunotherapy differentiates itself from chemotherapy and even targeted therapy. And so they picked PFS at 12 months. And I became involved at that point and it looked really good. I mean, if you look at the figures in the manuscript, the AUC is superb about their prediction and then what actually happened in the patient. And then in this paper, we applied it to a validation set of over 500 patients in a prospective trial, not randomized, it's called an observational trial. The investigator got to pick what they thought was the best therapy for that patient. And then in a blinded fashion, the proteomic assay experts did the analysis and applied it to the group.  And so what that means is some of the patients got chemotherapy alone, some got checkpoint immunotherapy monotherapy, some got in combination with chemotherapy. None of the patients in this study got a CTLA-4 inhibitor. That work is ongoing now. But what the study showed was that this assay can be used together with PD-L1 as what I would call a composite biomarker. You take the two together and it informs the oncologist about the meaning of that PD-L1. I'll give you an example. If that patient has a PD-L1 over 50% in their cancer and yet the PROphet test is negative, meaning less than 5 - it's a 0 to 10 scale - that patient for survival is better served by getting chemotherapy and immunotherapy. However, if the PROphet test is positive and the PD-L1 is over 50%, then the survival curves really look equivalent. As I said earlier, even in that group of patients, a lot of oncologists are reluctant to give them monotherapy. So if you have a test and the same sort of example is true for PD-L1 0, that you can differentiate. So this can really help inform the oncologist about what direction to go. And of course then you use your clinical judgment, you look at what you think of as the aggressiveness of the tumor or their liver metastases, etc. So again, that's how this test is being used for non-small cell lung cancer. And maybe I'll stop there and then I'll come back and add some other points. Dr. Rafeh Naqash: I definitely like your analogy of this therapy de-escalation strategy. Like you mentioned for PD-L1 high where the PROphet test is negative, then perhaps you could just go with immunotherapy alone. In fact, interestingly enough, I was invited to a talk at SITC a couple of weeks back and this exact figure that you're referring to was one of the figures in my slide deck. And it happened by chance that I realized that we were doing a podcast on the same paper today.  So I guess from a provocative question standpoint, when you look at the PD-L1 high cohort in the subset where you didn't see a survival difference for chemo plus immunotherapy versus immunotherapy alone, do you think any element of that could have been influenced by the degree of PD-L1 positivity above 50%? Meaning could there have been a cohort that is, let's say PD-L1 75 and above, and that kind of skews the data because I know you've published on this yourself also where the higher the PD-L1 above 50%, like 90% PD-L1 positivity survival curves are much better than 50% to 89%. So could that have somehow played a role? Dr. David Gandara: The first thing to say is that PD-L1 and the PROphet score, there's very little overlap. I know that sounds surprising, but it's also true for tumor mutational burden. There's very little overlap. They're measuring different things. The PD-L1 is measuring a specific regulatory protein that is applicable to some patients, but not all. That's why even in almost all of the studies, people with PD-L1 0 could still have some survival benefit. But in this case they're independent. And not in this paper, but in other work done by this group, the PROphet group, they've shown that the PROphet score does not seem to correlate with super high PD-L1. So it's not like the cemiplimab data where if you have a PD-L1 of greater than 90%, then of course the patient does spectacularly with monotherapy. The other thing that's important here is they had a group of around a little less than 100 patients that got chemotherapy alone. The PROphet score is agnostic to chemotherapy. And so that means that you're not just looking at some prognostic factor. It's actually clinical utility on a predictive basis. Dr. Rafeh Naqash: I think those are very important points. I was on a podcast a couple of days back. I think there's a theme these days we're trying to do for JCO Precision Oncology, we're trying to do a few biomarker based podcasts, and the most recent one that we did was using a tissue transcriptome with ctDNA MRD and you mentioned the composite of the PD-L1 and the PROphet test and they use a composite of the tissue transcriptome. I believe they called it the VIGex test as well as MRD ctDNA. And when your ctDNA was negative at, I believe, the three month mark, those individuals had the highest inflamed VIGex test or highest infiltration of T cells, STING pathway, etc. So are there any thoughts of trying to add or correlate tissue based biomarkers or ctDNA based correlations as a further validation in this research with the company? Dr. David Gandara: Right. So there are many things that are being looked at, various composites looking at the commutations that might affect the efficacy of immunotherapy and how they correlate with profit positivity or negativity. And I'll just give the examples of STK11 and KEAP1. As you know, there's some controversy about whether these are for immunotherapy, whether they're more prognostic or predictive. I'm one of the co-authors among many in the recently published Nature paper by Dr. Skoulidis and the group at MD Anderson which report that for KEAP1 positive especially, but also SDK11 mutated getting immunotherapy, that that's where the CTLA-4 inhibitors actually play the greatest role. So realizing that this is still controversial, there are preliminary data, not published yet, that'll be presented at an upcoming meeting, looking at many of these other aspects, P53, SCK11, KEAP1, other aspects, TMB, that's actually already published, I think in one of their papers. So yes, there's lots of opportunities.  The other cool thing is that this isn't a test, it's a platform. And so that means that the OncoHost scientists have already said, “What if we look at this test, the assay in a group of patients with small cell lung cancer?” And so I just presented this as a poster at the world conference in San Diego. And it turns out if you look at the biology of small cell, where neither PD-L1 nor TMB seem to be very important, if you look at the biology of small cell and you form an assay, it only shares 44 proteins out of the 388 with non-small cell. It's a different biology. And when we applied that to a group of patients with small cell lung cancer, again it had really pretty impressive results, although still a fairly small number of patients. So we have a big phase three study that we're doing with a pharmaceutical company developing immunotherapy where we are prospectively placing the PROphet test in a small cell trial.  The platform can also be altered for other cancer types. And at AACR, Dr. Jarushka Naidoo presented really impressive data that you can modify the proteins and you can predict immunotherapy side effects. So this is not like a company that says, “We have one test that's great for everything.” You know how some companies say, “Our test, you can use it for everything.” This company is saying we can alter the protein structures using AI machine learning assisted process to do it and we can have a very informed assay in different tumor types and different situations. So to me, it's really exciting. Dr. Rafeh Naqash: Definitely to me, I think, combining the AI machine learning aspect with the possibility of finding or trying to find a composite biomarker using less invasive approaches such as plasma or blood, definitely checks a lot of boxes. And as you mentioned, trying to get it to prospective trials as an integral biomarker perhaps would be likely the next step. And hopefully we see some interesting, exciting results where we can try to match or stratify patients into optimal combination therapies based on this test.  So now to the next aspect of this discussion, David, which I'm really excited about. You've been a leader and a mentor to many. You've led ISLC and several other corporate group organizations, et cetera. Can you tell us, for the sake of all the listeners, junior investigators, trainees, what being a mentor has meant for you? How your career has started many years back and how it's evolved? And what are some of the things that you want to tell people for a successful and a more exciting career as you've led over the years? Dr. David Gandara: Well, thank you for the question. Mentoring is a very important part of my own career. I didn't have an institutional mentor when I was a junior investigator, but I had a lot of senior collaborators, very famous people that kind of took me under their wing and guided me. And I thought when I basically establish myself, I want to give back by being a mentor to other people. And you wouldn't believe the number of people that I'm even mentoring today. And some of them are not medical oncologists, they're surgeons, they're radiation oncologists, they're basic scientists. Because you don't have to be an expert in that person's field to be a mentor. It helps, but in other words, you can guide somebody in what are the decision making processes in your career. When is it time to move from this institution onward because you can't grow in the institution you're in, either because it's too big or it's too small? So I established a leadership academy in the Southwest Oncology Group, SWOG. I've led many mentoring courses, for instance, for ISLC, now for International Society Liquid Biopsy, where I'm the executive committee liaison for what's called The Young Committee. So ISLB Society, totally devoted to liquid biopsy, six years old now, we have a Young Committee that has a budget. They develop projects, they publish articles on their own, they do podcasts. So what I'm saying is those are all things that I think opens up opportunities. They're not waiting behind senior people, they are leading themselves.  We just, at our International Lung Cancer Congress, reestablished a fellows program where a group of fellows are invited to that Huntington beach meeting. It's now in its 25th year and we spend a day and a half with them, mentoring them on career building. I'll just give you my first, I have the “Letterman Top 10”. So my first recommendation is if all you have is lemons, make lemonade. And what I'm meaning is find what you can do at your institution if you're a junior person, what you can claim to be your own and make the very best of it. But then as you get further along in my recommendations, one of them is learn when to say ‘no'. Because as a junior investigator the biggest threat to your career is saying ‘yes' to everybody and then you become overwhelmed and you can't concentrate. So I'll stop there. But anyway, yes, mentoring is a big part of my life. Dr. Rafeh Naqash: Well, thank you, David. This is definitely something that I'm going to try to apply to my career as well. And this has been an absolute pleasure, especially with all the insights that you provided, not just on the scientific side but also on the personal career side and the mentorship side. And hopefully we'll see more of this work that you and other investigators have led and collaborated on. perhaps more interesting plasma based biomarkers. And hopefully some of that work will find its home in JCO Precision Oncology. Thank you again for joining us today. Dr. David Gandara: My pleasure. Dr. Rafeh Naqash: And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service organization, activity or therapy should not be construed as an ASCO endorsement.   Dr. David Gandara Disclosures: Consulting or Advisory Role Company: Henlius USA, Foundation Medicine, Janssen Pharma, Merck & Co, Mirati Therapeutics, Regeneron, AstraZeneca, Guardant Health, Genentech, Exact Sciences  Research Funding Company: Amgen, Genentech, Astex Pharma  

Chris shares his first light report with the 7” TMB refractor. Shane joined Chris for second light with the 7” and the guys talk about the views. 

JCO PO authors Dr. Philippe Bedard (Staff Medical Oncologist at Princess Margaret Cancer Centre and Professor of Medicine at University of Toronto) and Dr. Alberto Hernando Calvo (Medical Oncologist at Vall d´Hebron University Hospital) share insights into their JCO PO article, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab,” one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Drs. Bedard and Hernando Calvo discuss how combined transcriptome and ctDNA longitudinal analysis associates with pembrolizumab outcomes. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today we are excited to be joined by Dr. Philippe Bedard, Staff Medical Oncologist at the Princess Margaret Cancer Center and Professor of Medicine at the University of Toronto, as well as by Dr. Alberto Hernando-Calvo, Medical Oncologist at the Vall d'Hebron University Hospital, both authors of the JCO Precision Oncology article titled, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.”  Thank you for joining us today. Phil and Alberto. Dr. Alberto Hernando-Calvo: Thank you. Dr. Philippe Bedard: Great to be with you. Thanks for having us.  Dr. Rafeh Naqash: One of the reasons we do this podcast, as some of the listeners who listen to this podcast regularly may know, is to bring in novel approaches and try to understand how the field is moving towards a space where we are understanding biomarkers better. So your manuscript that was published in JCO Precision Oncology fulfills many of those criteria. And interestingly enough, I was at a conference at the Society for Immunotherapy of Cancer last month earlier in November and a lot of excitement at SITC was revolving around novel transcriptomic biomarkers, proteomic biomarkers or imaging based biomarkers. So could you tell us a little bit about why you started looking at biomarkers? This is an extremely competitive field. Why did you think that looking at the transcriptome is somewhat different from or more interesting from tumor mutational burden PDL-1 than other biomarkers that we currently use? And that question is for you Alberto to start off.  Dr. Alberto Hernando-Calvo: So I think gene expression profiles may have a predictive performance as compared to already existing biomarkers and this was one of the points that we describe in our manuscript. The gene expression signature that we developed back in 2019 at Vall d'Hebron Institute of Oncology was initially developed based on over 45 different tumor types and tested in over 1000 patients treated with antiPD-1 and anti PDL-1. And back then and in this manuscript, we proved that for instance the gene expression signature VIGex that we developed has a potential complementary role to other predictive biomarkers. In this case, we observe this predictive power with ctDNA dynamics and we then see a correlation with other existing biomarkers such as tumor mutational burden. So I don't think we need to use one or the other, but rather they may have additive predictive power. So we need to better individualize predictive biomarkers based on tumor types and select the best combination possible to improve the performance.  Dr. Rafeh Naqash: I completely agree that one size does not fit all, especially in the landscape of immunotherapy. From your perspective, when you developed the original signature, how did you choose what genes to look at? I looked at the manuscript, on the methodology side, some of the signatures are pro-inflammatory STING interferon gamma based, so how did you try to identify that these are the 7 to 10 or whatever number of signatures on the transcriptome side? And then why did you try to combine it with ctDNA based changes?  Dr. Alberto Hernando-Calvo: Back in our initial manuscript, published in Med from Cell Press, we developed the VIGex gene expression signature, as I mentioned, with taking into consideration over 1000 tumor samples from FFPE that we can consider real world samples because they are from real patients coming from the clinic notes as part of real investigational protocol doing or performing biopsies on patients. We did observe after doing a VIGex research and doing different tests, we eventually collected these 12 different genes. Because there is a combination of both genes involved in the interferon gamma pathway, we have genes associated with Tregs as well as T cell memory cells. So it's not only looking at genes that are associated with T cell activation or CD8+ T cell infiltration, but also looking at genes that may be overactivated, overexpressed, an immunosuppressive tumor microenvironment. So it was both selecting genes, the minimum number of genes to do it more scalable and having the minimum dataset of genes and including in the signature genes that are already at targets for immune sequent inhibitors or are being tested in immunotherapy combinations.  Dr. Rafeh Naqash: Thank you. And Phil, for the sake of our listeners, could you elaborate upon this aspect of using ctDNA? So this was tumor-informed ctDNA from what I understood in the manuscript. You guys basically try to use it to understand changes in the ctDNA with treatment and then try to combine it with the transcriptome signature. How did the idea come up initially and how did you plan on combining this with an RNA-based signature? Because I have seen manuscripts and other data where people are either using one or the other, but not necessarily both together. So how did you guys come up with that idea? Dr. Philippe Bedard: Well, we thought that this was a great opportunity to look at the combination of the transcriptome as well as the ctDNA dynamics because we had run an investigator-initiated phase 2 clinical trial called INSPIRE at our institution at Princess Margaret from 2016 to 2018, where patients across five different tumor groups received single agent pembrolizumab. And we really did a deep dive on these patients where there were tumor biopsies before and while on treatment. We did exome sequencing, we did RNA sequencing to capture the transcriptome. And in a prior analysis, we had partnered with Natera to look at their Signatera assay, which is a bespoke ctDNA assay, to look at ctDNA dynamics using this test and the association with response outcomes as well as survival outcomes. So we thought that this was a really unique data set to try and address the question of whether or not there was complementarity in terms of looking at the transcriptome and transcriptome signatures of IO benefit together with the ctDNA dynamics. Dr. Rafeh Naqash: From a patient treatment standpoint, it sounded like you mostly tried to include individuals who were treated with pembrolizumab. Did this not include individuals who were treated with chemoimmunotherapy or chemotherapy with pembrolizumab? Just pembrolizumab alone? And if that's the case, some of the tumor types there included, from what I remember, ovarian cancer and some other unusual cancers that don't necessarily have approvals for single agent pembrolizumab, but perhaps in the TMB-high setting. So can you elaborate on the patient selection there for the study?  Dr. Philippe Bedard: Yeah, that's a great question. So at the time that the study was designed in 2015, this was really the early days of immune checkpoint inhibitor therapy, so we didn't have the approvals that we have now in specific tumor types for immunotherapy and chemotherapy combinations. So when the study was designed as an investigator initiated clinical trial, the idea was really to capture patients across different tumor types - so head and neck squamous cell carcinoma, malignant melanoma, ovarian cancer, triple negative breast cancer, and a kind of mixed histology solid tumor cohort, where we knew that there were some patients who were going to be immunotherapy responsive, where there was already approvals or evidence of single agent activity, and others where the responses were more anecdotal, to try and understand in a phase 2 clinical trial with kind of a deep dive, which patients benefited from treatment and which didn't. Dr. Rafeh Naqash: Interesting approach. Going to the results, Alberto, could you help us understand some of the important findings from these data? Because there's different sections of how you tried to look at the response rates, the survival, looking at the immune deconvolution, if you could explain that. Dr. Alberto Hernando-Calvo: So the first thing that we tried was to further confirm the external validation of this immune gene expression signature, VIGex in the INSPIRE asset. So what we observed at VIGex-Hot, the category defined by VIGex-Hot tumor microenvironment, was associated with better progression free survival. After including that in a multivariable analysis adjusted by other biomarkers such as TMB, PDL-1 or tumor type, this was also confirmed for overall survival. So then the next step was to really try to hypothesize if the addition of ctDNA dynamics, taking into consideration the ctDNA quantification at baseline as compared to cycle three, if those dynamics could further improve the predictive performance of VIGex categories taken in the baseline samples. What we did observe was that, for instance, VIGex-Hot tumors in baseline tumor samples that were having a ctDNA decrease, as I mentioned before on cycle three assessment as compared to baseline, were having both better progression free survival and better prognosis overall. Another important finding was the evaluation of response rate across tumor types considering both biomarkers. I would say the most important finding is that when we were considering a cold tumor microenvironment in baseline samples before pembrolizumab initiation plus an increase in ctDNA values, what we observed is that those patients were having a 0% response rate. So this may help as a future strategy either for intensification of immunotherapy regimens in a more individualized way or for an early stop to immunotherapy and try to avoid financial toxicities as well as toxicities for our patients. Dr. Rafeh Naqash: From the data that you showed, it seems that there was a strong correlation, as you sort of mentioned, between individuals that had ctDNA clearance and baseline immune pro-inflammatory signatures. So do you really need the transcriptome signature or could the ctDNA just serve as an easy quick surrogate? Because from a cost standpoint, doing whole transcriptome sequencing or more RNA sequencing or tissue standpoint, where tissue is often limited, can become a big issue. So do you think that validation of this may perhaps more revolve around using ctDNA as an easier metric or surrogate? Or am I overestimating the utility of ctDNA? Dr. Philippe Bedard: I think it's a really good question. In our data set which was relatively small, there were 10 patients who had ctDNA clearance, meaning ctDNA that was positive at baseline was not detected. And so 9 out of those 10 patients, as you alluded to, were VIGex-Hot. So the question is a good one, could you do the same with just ctDNA clearance alone, particularly in identifying these patients who really do well, who have long term disease control on immunotherapy? I think it's a tough question to answer because the field is also changing in terms of sensitivity of detection of ctDNA tests. So we know now that there are newer generations of tests which can detect even at logs down in terms of allele variants in the circulation. So I think we need more data to address the question. I think it is important as to what is the best test, what is the endpoint that we should be using from a drug development point of view in terms of really trying to push and understand which treatment regimens are the most effective and have early readouts in terms of activity. Because we all recognize in the clinic that radiographic response doesn't tell the whole story, especially early radiographic assessments using RECIST or other criteria that we apply in clinical trials. Dr. Rafeh Naqash: From a clinical trial standpoint, we often talk about validation of these studies. You may have heard of other tests where, for example, the NCI iMatch, which is incorporating transcriptome sequencing based approach to stratify patients as an integral biomarker for treatment stratification. Is that something that you guys are thinking of using, this approach where individuals who are signature highly inflamed perhaps get lesser therapies or there's a de-intensification of some sort similar to what people are trying to do with ctDNA-based approaches? Dr. Philippe Bedard: I think that's a great question. I think it makes a lot of sense. And certainly, with the new wave antibody drug conjugates in terms of identifying patients who have expression of targets for antibody drug conjugates, that's very attractive as an approach because we don't necessarily have IHC markers for all of the different targets of antibody drug conjugates. We don't necessarily have IHC markers to completely understand different contributions to the tumor microenvironment and whether or not tumors are inflamed. But it's also a challenging approach too because RNA-seq currently is not a routine clinical test. Sometimes there are issues, particularly in patients who have stored specimens that are formalin-fixed and paraffin-embedded in terms of the quality of the RNA for RNA sequencing. And it's not always feasible to get pre-treatment biopsies and turn them around in an approach. So I think it is an attractive approach for clinical trials, but it's a hypothesis that needs to be tested. It's not something that is ready for clinical prime time today in 2024. Dr. Rafeh Naqash: One of the other interesting observations that I came across in your manuscript was that tumor mutational burden, interestingly, did not correlate with signature high tumors. What is the explanation for that? Because generally you would expect a TMB high to perhaps also have an immune gene high signature. Could it have something to do with the tumor types because there was a heterogeneous mixture of tumor type? Or I'm not sure. What else could you possibly think of that you didn't see those correlations or just sample size limitations? Dr. Alberto Hernando-Calvo: Yes. So our findings are consistent with prior data suggesting for instance T cell inflamed gene expression profile was also not correlated with tumor mutational burden and both biomarkers in a prior publication. So to have additive predictive performance for identifying patients most likely to benefit from anti PD-1 regimen, so we somehow were expecting this observation, the fact that both biomarkers are not very correlated. Dr. Rafeh Naqash: So given the proof of concept findings from your study, Phil, what is the next interesting step that you guys are thinking of to expand this? Would you think that a nivolumab-ipilimumab treated cohort would have similar findings? Or is this a treatment specific single agent immunotherapy specific correlation that you found versus something else that you may find in a nivo-ipi cohort or a doublet immune checkpoint cohort?  Dr. Philippe Bedard: The findings are really hypothesis generating. They require additional validation. And you're quite right, there may be nuances in terms of specific tumor types, combinations with other immunotherapy or combinations with chemotherapy or other agents. So I think it would be great if there are other data sets that are collecting this type of information that have ctDNA dynamics and also have transcriptome and potentially exome or genome analysis to look at these types of questions because the field is moving quickly and we really need more data sets in order to understand some of the nuances and greater numbers to validate the signals that we see. Dr. Rafeh Naqash: And one thing, as you said, the field is definitely moving very quickly. I was meeting with a company an hour back and they have an imaging-based approach using fresh tissue to look at pharmacodynamic biomarkers. And I used to work in the NCI with a group that was very interested and they developed an immuno-oncology pharmacodynamic panel that has been used and published in a few clinical trials where they did phosphorylation status. So the final theme that comes out of most of these research based studies that are being done is that one size does not fit all. But the question that comes to my mind is how many things do you necessarily need to combine to get to a predictive biomarker that is useful, that is patient centric, and that perhaps is able to identify the right therapy for the right patient. What is your take on that, Phil?  Dr. Philippe Bedard: Yeah, that's a great question too. The challenge is it depends on the context in terms of what degree of positive predictive value do you need as well as the negative predictive value to drive clinical decisions. So I think in certain situations where you don't have other approved treatment options and with a therapy that is potentially low toxicity and low financial toxicity, then I think the bar is very high in terms of being able to really confidently identify that patients aren't going to benefit. I think the nuance and the challenge becomes when you move into earlier lines of therapy, or when you talk about combinations of agents, or trying to understand within the context of other available options, particularly with treatments that have significant side effect profiles as well as financial risks, then it becomes a much more nuanced question and you really need comparative studies to understand how it fits versus the existing treatment paradigm. So I'm not really answering your question with a specific number because I think it's hard to give you a number. Some of that we also need input from patients in terms of what kind of level of validation do you need and what kind of level of discrimination do you need in order to drive decisions that are meaningful for them. Dr. Rafeh Naqash: Definitely early days, as you pointed out. More and more work in this field will hopefully lead us in the direction that we all want to go in.  Now, going to a different aspect of this podcast, which is trying to understand the trajectories for both of you, Phil and Alberto. And as you mentioned, this project seemed to have started in 2015. So I'm guessing there's a history there between Princess Margaret and Vall d'Hebron. Could you highlight that a little bit? And then perhaps, Alberto, after that you could tell us a little bit about your career when you worked at Princess Margaret as a fellow and then now back at Vall d'Hebron. Phil, you as well. Dr. Philippe Bedard: So absolutely. We have a long history of collaborating with Vall d'Hebron in Barcelona. It's really a great cancer institution with a lot of like minded individuals. We have a formal partnership and we have a lot of informal links in terms of scientists and clinicians who we work with and who we collaborate with on early phase clinical trials, as well as through different investigator networks and other translational projects. So this was really how this collaboration came about and we were fortunate to have Alberto, who came to work with us for two years and brought this great idea of looking at this signature they had developed at Vall d'Hebron in their phase one group and applying it to a data set that we had through the INSPIRE clinical trial.  Dr. Rafeh Naqash: Sounds like a very successful academia-academic collaboration, which is very nice to see. So, Alberto, could you tell us a little bit about your career trajectory and how you ended up at Princess Margaret and then back at Vall d'Hebron and what you do currently? Dr. Alberto Hernando-Calvo: Yes. So I did my oncology residency at Vall d'Hebron in Barcelona, Spain. Then I decided to further specialize in early drug development as well as head and neck cancer oncology. So I decided to pursue a clinical research fellowship under the supervision of Phil Bedard, among others. And so we decided to further validate the signature that we had developed both in the cancer genomic lab at Vall d'Hebron Institute of Oncology and the phase one unit at Vall d'Hebron, and apply the signature that have been originally tested in patients receiving anti PD-1 or anti PDL-1 combinations in early phase clinical trials. In the phase 2 clinical trial of INSPIRE, where we also had ctDNA dynamics and allowed us to test both biomarkers and see that additive predictive power when we were using both. That was one of my research topics under the mentorship of Dr. Bedard and my fellowship at Princess Margaret. And this was one of the manuscripts describing all the findings of this collaboration between Vall d'Hebron and Princess Margaret Cancer Center. Dr. Rafeh Naqash: And then, Phil, if you could highlight some of the things that you've done over the course of your career and perhaps some advice for early career junior investigators and trainees.  Dr. Philippe Bedard: I finished my oncology, medical oncology training at the University of Toronto in 2008. And then I did a breast cancer fellowship in Brussels at Breast International Group. At the time, I was really intrigued because it was really kind of the early days of microarray and RNA signatures in terms of expressing signatures were being used as part of a clinical trial that BIG was running called the MINDACT Study. And so when I finished my fellowship, I came back to Princess Margaret, started on staff. I've been here now for 15 years. I was fortunate to work with the phase 1 group and kind of my career has sort of morphed in terms of early drug development as well as genomics. I've been involved with the American Association for Cancer Research project GENIE, where I'm the current chair. This is really an international data sharing project with panel based sequencing, which both Princess Margaret and Vall d'Hebron have contributed to. And I've been fortunate to work with a number of really talented early career investigators like Alberto, who spend time with us in our drug development program and launched transitional research projects that leverage some existing data sets at their own institutions and also bring together with different research groups at our institution to lead to publications like this one. Dr. Rafeh Naqash: Thank you so much. This was very exciting. Phil and Albert, thanks for joining us today and thank you for allowing us to discuss your interesting manuscript and hopefully we'll see more of this biomarker work from you guys in the near future, perhaps published in JCO Precision Oncology.   And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this episode, I chat to Victoria Maskell about my biggest manifestation secret! Here we discuss all things TBM and how things have changed for me on my TBM journey. If you would like to sign up for TMB, use my code: ANNEKA to get 15% off membership. To find Victoria online: Tik Tok and Instragram: @victoria.maskell Email: victoria@victoriamaskell.com Website: victoriamaskell.com To find me online: Tik Tok: @coachingbyanneka_official Instagram: @coachingbyanneka Email: thrive@coachingbyanneka.co.uk Find all of my products on my Stan Store link below. This includes my Alcohol-Free Christmas Survival Guide, and links to apply for coaching and my other courses: https://stan.store/Coachingbyanneka

Send us a textLevi, TMB, and Marchie are here to preview the Big 12 Championship game vs. Arizona State.

No one's going hungry this week with your beloved TMBTL of the Dog hosts on the case. That's right, Lindy and Meagan have teamed up once again with Luke and Andrew of Too Beautiful to Live to bring you another episode that will take you on several journeys involving puppies in witness protection, Meagan's little buggies, Luke's homicidal tendencies, and Andrew's connection to a famous TMB earworm involving dogs, shit, and peach pits.In other words, a perfectly normal crossover event hosted by four well-adjusted adults who don't have any problems at all. New to Too Beautiful to Live? Check them out here: https://www.tbtl.net/ Do you have brain problems that would fit right in on an episode of TMBTL of the Dog? Tell us all about it deartextmeback@gmail.com. Or you can text or call us at the Best Friend Party Phone: (703) 829-0003 or DM us @textmebackpod on IG and Tiktok.Also! This is our last episode of 2024 but there will still be lots of fun things on our Patreon! Be sure to subscribe for goodies. Everyone else, we'll see your asses in 2025!STUFF TO CHECK OUT:Link to Lindy's masterclass!Gift a Lindy Cameo! She'll talk your loved one's ear off and it'll be delightful!Check out Meagan's new newsletter, SWAMP PERSON! It will make you laugh AND offer actionable insights to get us through what's coming.Subscribe to Lindy's newsletter butt newsCheck out our MERCH! (Patrons get a discount, so check us out at patreon.com/textmebackpod)⋆｡°✩⋆｡°✩⋆｡°✩⋆｡°If you like this episode and want us to keep making the show forever, please subscribe to our Patreon. This podcast will always be free, but we need your help to produce it -- and if you support our Patreon, you'll get all kinds of goodies in addition to the show itself! Learn more about the different tiers and rewards here: https://www.patreon.com/TextMeBackPodAlso! Please keep in touch with us! You can text OR CALL us at the Best Friend Party Phone: (703) 829-0003.We're on Instagram at @textmebackpod!Full videos of our episodes are on YouTube at @textlindyandmeaganbackYou can email us at deartextmeback@gmail.com!WE WANT TO HEAR FROM YOU SO BAD!⋆｡°✩⋆｡°✩⋆｡°✩⋆｡°TEXT ME BACK is a production of Lindy West and Meagan Hatcher-Mays, proud members of the BFF Network. Our senior producer is Meagan Hatcher-Mays. Our other senior producer is Lindy West. Our show is supported by COPILOT Collective and produced by Alli Slice.Our music is by Chief Ahamefule J. Oluo. Diana Bowen is our video and creative advisor. Our digital strategist is Chance Nichols.You can also follow the podcast on Instagram and TikTok @textmebackpod. And for even more bestie content, follow Lindy and Meagan on Instagram at @thelindywest and @importantmeagan!Special thanks as always to our perfect angels: Jeannie Yandel, Brandi Fullwood, and Isolde Raftery.⋆｡°✩⋆｡°✩⋆｡°✩⋆｡°See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Send us a textThis week, Levi, Marchie, and TMB are back to talk about the Cyclones' victory over Cincinnati last weekend and how Iowa State can stay alive in the Big 12 championship game race with a win at Utah this weekend. The guys also break down a number of tiebreaker scenarios so you know who to root for this weekend.

Send us a textLevi, March, and TMB are back to preview this weekend's game as your 7-0 Iowa State Cyclones control their own destiny as they work towards a Big 12 title game berth.

Following an epic Asia Trail Master Finals at TMB in Borneo, we recap the event and catch up with male champion Jeff Campbell.Check out all the footage from ATM Finals:ATM Facebook Male final Podium winners videoMale Podium:Jeff Campbell - 09:49Hisashi Kitamura - 09:51Arnie Macarenes - 09:56Female Podium:Priya Rai - 11:00Vanja Cnops - 12:36Rashila Tamang - 13:13

Send us a textThis week, Levi, Marchie, and TMB are back to kick off the 2024 football season with an analysis of the first depth chart and a preview of North Dakota, as well as our predictions for the week.

Una dieta de 1200 calorías al día es generalmente insuficiente para cualquier persona adulta por varias razones, relacionadas tanto con la salud física como mental:1. Requerimientos energéticos básicos:Tasa Metabólica Basal (TMB): La mayoría de los adultos necesitan más de 1200 calorías al día solo para mantener las funciones corporales básicas en reposo, como respirar, mantener la temperatura corporal, y la circulación sanguínea. La TMB varía según factores como la edad, el sexo, el peso, y la masa muscular, pero generalmente supera las 1200 calorías en la mayoría de las personas.Actividad diaria: Además de la TMB, el cuerpo necesita energía adicional para realizar cualquier actividad diaria, como caminar, trabajar, o realizar ejercicios. Una dieta de 1200 calorías generalmente no proporciona suficiente energía para estas actividades, lo que puede llevar a una fatiga extrema y una reducción en la capacidad para realizar tareas diarias.2. Desnutrición y deficiencias nutricionales:Insuficiencia de nutrientes esenciales: Una dieta tan baja en calorías hace difícil consumir cantidades adecuadas de nutrientes esenciales, incluyendo vitaminas, minerales, proteínas, grasas saludables, y carbohidratos. Esto puede llevar a deficiencias nutricionales que afecten la salud a corto y largo plazo, causando problemas como anemia, debilidad muscular, y debilitamiento del sistema inmunológico.Pérdida de masa muscular: Con una ingesta tan baja en calorías, el cuerpo puede comenzar a descomponer tejido muscular para obtener energía, especialmente si no se consume suficiente proteína. La pérdida de masa muscular puede disminuir el metabolismo y dificultar la pérdida de peso a largo plazo.3. Efectos psicológicos y emocionales:Relación poco saludable con la comida: Seguir una dieta tan restrictiva puede promover una relación poco saludable con la comida, llevando a comportamientos alimentarios desordenados, como el trastorno por atracón o la obsesión por la restricción.Estrés y ansiedad: La restricción calórica severa puede aumentar los niveles de estrés y ansiedad, ya que el cuerpo está constantemente en un estado de privación. Esto puede tener efectos negativos en la salud mental y en la capacidad para mantener hábitos saludables a largo plazo.4. Impacto negativo en el metabolismo:Ralentización metabólica: Cuando el cuerpo recibe menos calorías de las necesarias, entra en un "modo de ahorro de energía," reduciendo la tasa metabólica basal para conservar energía. Esto puede hacer que sea más difícil perder peso y más fácil ganarlo de nuevo una vez que se aumenta la ingesta calórica.Efecto rebote: Las dietas extremadamente bajas en calorías pueden llevar a un efecto rebote, donde la persona recupera el peso perdido, o incluso más, una vez que vuelve a una ingesta calórica normal, debido a la ralentización metabólica y la recuperación del apetito.5. Riesgos para la salud a largo plazo:Problemas hormonales: La ingesta insuficiente de calorías puede afectar el equilibrio hormonal, lo que puede causar irregularidades menstruales en mujeres, problemas de fertilidad, y otros desequilibrios hormonales.Salud cardiovascular: Una dieta insuficiente en calorías y nutrientes esenciales puede aumentar el riesgo de desarrollar problemas cardiovasculares, debido a la falta de grasas saludables y otros nutrientes importantes para la salud del corazón.En resumen, una dieta de 1200 calorías al día es generalmente insuficiente para la mayoría de los adultos porque no cubre las necesidades energéticas básicas, puede llevar a deficiencias nutricionales, afectar negativamente la salud mental, y provocar problemas metabólicos y hormonales. Es importante seguir una dieta que esté adaptada a las necesidades individuales y que promueva una relación saludable con la comida y el cuerpo.Conviértete en un seguidor de este podcast: https://www.spreaker.com/podcast/comiendo-con-maria-nutricion--2497272/support.

In this episode, Gregory Huhn, MD, MPHTM, presents a case study of a person with a long HIV treatment history, exploring when and how to consider agents with novel mechanisms of action.Listen as he discusses:The importance of engaging with patients to understand their perspectives and improve their satisfaction with their HIV careOptions in people with multiclass resistanceStudies of agents with novel mechanisms of action:BRIGHTE (fostemsavir)TMB-301/-311 (ibalizumab)CAPELLA (lenacapavir) Faculty​​Gregory Huhn, MD, MPHTM,Interim Chief, Division of Infectious DiseasesSenior Director of HIV ServicesCook County HIV Integrated ProgramsInterim Medical Director, The RMR CORE CenterProfessor, Division of Infectious DiseasesRush University Medical CenterChicago, IllinoisFollow along with the slides.https://bit.ly/4fHmxg5Get access to all of our new podcast episodes. Subscribe to the CCO Infectious Disease podcast on Apple Podcasts, Google Podcasts, or Spotify.    

Neste episódio do Arsenal de Mentores, eu conto com a ajuda do meu amigo e sócio Rafa Leite (@orafaleite), para entrevistar o grande Renato Torres (@orenatotorres), que vem fazendo coisas revolucionárias no mercado. Renato é fundador d'O Corpo Explica, da TMB e de outras empresas, e, com sua vasta experiência em tecnologia, marketing e vendas, tem estruturado processos comerciais altamente efetivos. No episódio #032, ele nos conta como saiu da falência para alcançar os sonhados lançamentos de múltiplos 8 dígitos, compartilha conosco suas vivências e ensina a estruturar times e processos comerciais que realmente dêem resultado.   Dê o play e escute agora ao episódio completo!

The 13th episode of TMB's "Weekend Hangover" with Ricky-Bobby and Dustin along with our special guest will be talking all things related to the GP races at Sachsenring. We're also planning a bit of a Laguna Seca Preview. Lets explore the story lines of the weekend. What's up with Joe Roberts and the busted wing? How about those Trackhouse dudes?? Why does MM93 suck in Q, and much much more! Lets get into it!! AND... Like always, we've got a secret special guest joining the show to weigh in. Who's it going to be?? Enjoy!! Like / Subscribe / Comment / Share..... ** ROCKWELL WATCHES: Check out their website https://rockwelltime.com/ Enter the code "TDZ20" at checkout and save 20% on a new Rockwell!! Sign up for your next TrackDaz event here: http://www.trackdaz.com *PIRELLI TIRES!! ** You can get your Pirelli rubber from us directly on our registration site. Next event is July 23rd at Laguna Seca!!. This is a bucket list track for sure, especially at the 105db limit. Lets make some noise, and have fun ripping the cork screw. Sign up here: http://www.trackrabbit.com/s/2kxu Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdaz Follow the TrackDaz Crew: @chili144 @jimmyz853 @phen2210 @gil823 @formula_r @chili144 @lgbrown_ @dkm60 @canea121 @g_offsims @ricardo.abueg @trackdazkaren @fharo3 @modbaez @m39023 @dreek46 @bubblesrides @r6_krissy_P

Welcome back Cyclone fans! The 2024 season is upon us, and Levi, Marchie, and TMB are back to analyze the Iowa State roster.

This episode of TMB's "Weekend Hangover" with Ricky-Bobby and Dustin has reached 12 episodes already!! Crazy!! We're planning chat about all of the racing storylines of the weekend. Topics include the MotoGP and Rookies Cup races at Assen, along with MotoAmerica races at the Ridge. Lets get into it!! AND... Like always, we've got a secret special guest joining the show to weigh in. Who's it going to be?? Enjoy!! Like / Subscribe / Comment / Share..... ** ROCKWELL WATCHES: Check out their website https://rockwelltime.com/ Enter the code "TDZ20" at checkout and save 20% on a new Rockwell!! Sign up for your next TrackDaz event here: http://www.trackdaz.com *PIRELLI TIRES!! ** You can get your Pirelli rubber from us directly on our registration site. Next event is July 23rd at Laguna Seca!!. This is a bucket list track for sure, especially at the 105db limit. Lets make some noise, and have fun ripping the cork screw. Sign up here: http://www.trackrabbit.com/s/2kxu Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdaz Follow the TrackDaz Crew: @chili144 @jimmyz853 @phen2210 @gil823 @formula_r @chili144 @lgbrown_ @dkm60 @canea121 @g_offsims @ricardo.abueg @trackdazkaren @fharo3 @modbaez @m39023 @dreek46 @bubblesrides @r6_krissy_P

Jim Boston of Boston & Hughes, PC reviews the differences between a lawsuit and a Texas Medical Board (TMB) case; how board complaints are filed and what to expect; common patient complaints; and some best- and worst-case scenarios when faced with a TMB complaint.

This is the 11th episode of TMB's "Weekend Hangover" with Ricky-Bobby and Dustin. In this one, we chat about all of the racing storylines of the weekend. Topics include the WorldSBK action at Misano.. Is Toprak superman? In MotoAmerica its the Bobby, Mathew, Hayden Show for the most part. Lets get into it!! AND... Like always, we've got a secret special guest joining the show to weigh in. Who's it going to be?? Enjoy!! Like / Subscribe / Comment / Share..... ** ROCKWELL WATCHES: Check out their website https://rockwelltime.com/ Enter the code "TDZ20" at checkout and save 20% on a new Rockwell!! Sign up for your next TrackDaz event here: http://www.trackdaz.com *PIRELLI TIRES!! ** You can get your Pirelli rubber from us directly on our registration site. Next event is June 29-30th weekend. We're going to do Config 13 CW Saturday, and Config 1 CCW on Sunday. Saturday night is also a Motorbike swap meet!! Sign up here: http://www.trackrabbit.com/s/2ksi Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdaz Follow the TrackDaz Crew: @chili144 @jimmyz853 @phen2210 @gil823 @formula_r @chili144 @lgbrown_ @dkm60 @canea121 @g_offsims @ricardo.abueg @trackdazkaren @fharo3 @modbaez @m39023 @dreek46 @bubblesrides @r6_krissy_

the 10th episode of TMB's "Weekend Hangover" with Ricky-Bobby and Dustin. In this one, we chat briefly on the MotoAmerica races at Road America, Rookies Cup, and of course all the GP stuff. Joe Roberts showing American riders kick ass, MotoGP Musical Chairs, Rain and Sunshine in Cheeseland... of course we'll talk Baggers!! Oh, and we've got a special guest like always! Like/Subscribe/Comment/Share/ all that, but most importantly, enjoy. ** ROCKWELL WATCHES: Check out their website https://rockwelltime.com/ Enter the code "TDZ20" at checkout and save 20% on a new Rockwell!! Sign up for your next TrackDaz event here: http://www.trackdaz.com *PIRELLI TIRES!! ** You can get your Pirelli rubber from us directly on our registration site. Next event is June 29-30th weekend. We're going to do Config 13 CW Saturday, and Config 1 CCW on Sunday. Saturday night is also a Motorbike swap meet!! Sign up here: http://www.trackrabbit.com/s/2ksi Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdaz Follow the TrackDaz Crew: @chili144 @jimmyz853 @phen2210 @gil823 @formula_r @chili144 @lgbrown_ @dkm60 @canea121 @g_offsims @ricardo.abueg @trackdazkaren @fharo3 @modbaez @m39023 @dreek46 @bubblesrides

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss promising combination therapies and other compelling advances in genitourinary cancers in advance of the 2024 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of genitourinary cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode. Jeanny, it's great to have you on the podcast. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal. It's a pleasure to be here. Dr. Neeraj Agarwal: So, Jeanny, let's start with some bladder cancer abstracts. Could you tell us about the Abstract 4509 titled, “Characterization of Complete Responders to Nivolumab plus Gemcitabine Cisplatin versus Gemcitabine Cisplatin Alone in Patients with Lymph Node Only Metastatic Urothelial Carcinoma from the CheckMate 901 Trial.”  Dr. Jeanny Aragon-Ching: Of course, Neeraj, I would be delighted to. First, I would like to remind our listeners that the CheckMate 901 trial was a randomized, open-label, phase 3 study, in which this particular sub-study looked at cisplatin-eligible patients with previously untreated, unresectable, or metastatic urothelial carcinoma who were assigned to receive the combination of gemcitabine and cisplatin, followed by up to 2 years of nivolumab or placebo. Based on the data presented at ESMO 2023 and subsequently published in the New England Journal of Medicine, which shows significantly improved progression-free survival and overall survival in patients receiving the combination of gemcitabine, cisplatin, and nivolumab, this regimen was approved in March 2024 as a first-line therapy for patients with unresectable or metastatic urothelial carcinoma.  In the abstract that will be featured at ASCO this year, Dr. Matt Galsky and colleagues present a post-hoc analysis that aims to characterize a subset of patients with complete response as well as those with lymph node-only metastatic disease. In patients receiving the experimental treatment, 21.7% achieved a complete response, while 11.8% of the patients in the control arm achieved a complete response.  Among these complete responders, around 52% had lymph- node-only disease in both arms. Furthermore, when characterizing the subgroup of patients with lymph-node-only disease, those receiving the combination of gemcitabine-cisplatin plus nivolumab had a 62% reduction in the risk of progression or death and a 42% reduction in the risk of death compared to those treated with gemcitabine-cisplatin alone.  The median overall survival in the experimental arm in this subgroup was around 46.3 months, while it was only 24.9 months in the control arm. The ORR in patients with lymph-node-only disease receiving gem-cis plus nivo was about 81.5% compared to 64.3% in those treated with gem-cis alone. Dr. Neeraj Agarwal: Thank you, Jeanny, for the excellent summary of this abstract. We can say that nivolumab plus gemcitabine-cisplatin induced durable disease control and clinically meaningful improvements in OS and PFS compared to gem-cis alone in patients with lymph- node-only metastasis, and deserves to be considered as one of the options for these patients.  In a similar first-line metastatic urothelial carcinoma setting, Abstract 4502, also reported data on a recently approved combination of enfortumab vedotin and pembrolizumab. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, as quick reminder to our audience, this regimen was tested in the EV-302 phase 3 trial, where patients with previously untreated, locally advanced or metastatic urothelial carcinoma were randomized to receive enfortumab vedotin, plus pembrolizumab or gemcitabine plus either cisplatin or carboplatin. These data were also first presented at ESMO 2023 and subsequently published in the New England Journal of Medicine. They showed that this immune based combination significantly improved both progression free survival and overall survival, which were the primary endpoints compared to chemotherapy. In this abstract, Dr. Shilpa Gupta from the Cleveland Clinic and colleagues present the results of patient reported outcomes based on quality-of-life questionnaires in this trial.  Time to pain progression and time to confirm deterioration were numerically longer in patients treated with EV plus pembro, and patients with moderate to severe pain at baseline receiving this combination had a meaningful improvement in the Brief Pain Inventory Short-Form worst pain from week 3 through 26. Dr. Neeraj Agarwal: Thank you, Jeanny. This means that patients treated with EV plus pembro did not only have improved survival compared with platinum-based chemotherapy, but also improvement in their quality-of-life and functioning, further supporting the value of this combination for patients with locally advanced or metastatic urothelial carcinoma. This is terrific news for all of our patients.   Before we wrap up the bladder cancer section, would you like to tell our listeners about Abstract 4565, which provides the data on the efficacy of trastuzumab deruxtecan in patients with bladder cancer? Dr. Jeanny Aragon-Ching: Yes, Neeraj; this is timely given the recent FDA approval, which we will talk about. The abstract is titled, “Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2 Expressing Solid Tumors: Results from the Bladder Cohort of the DESTINY-PanTumor02 Study.” And as a quick reminder, the DESTINY-PanTumor02 was a phase 2 open-label study where trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2 expression on cancer cells, was evaluated in patients with HER2-expressing locally advanced or metastatic disease who previously received systemic treatment or who had no other treatment options. The expression of HER2 was evaluated on immunohistochemistry by local or central testing.   The primary endpoint was confirmed objective response rate by investigator assessment. Secondary endpoints included duration of response, progression free survival, disease control rate, and safety. The primary analysis, which was published in the Journal of Clinical Oncology, showed an ORR of 37.1% and responses across all cohorts and the median duration of response was 11.3 months. Based on these results, fam-trastuzumab deruxtecan-nxki was just granted accelerated FDA approval for unresectable or metastatic HER2-positive solid tumors in April 2024.  So, back to this abstract; Dr. Wysocki and colleagues report the results of the bladder cancer cohort. This study included 41 patients with urothelial cancer and at a median follow up of around 12.6 months, the objective response rate among these patients was 39%, the median PFS was 7 months, and the duration of response median was 8.7 months. The disease control rate at 12 weeks was around 71%. Regarding the safety profile, 41.5% of patients experienced grade ≥3 drug related adverse events and interstitial lung disease or pneumonitis did occur in about 4 patients. Although there was no statistical comparison between different groups, the ORR was numerically highest among the HER2 3+ group with 56.3%.  Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data support consideration of trastuzumab deruxtecan as a salvage therapy option for pre-treated patients with HER2 expressing urothelial cancers and show that we are extending our treatment options to include therapies with novel mechanisms of action. This is definitely exciting news for patients with bladder cancer. Dr. Jeanny Aragon-Ching: Yes, absolutely, Neeraj. Now, let's switch gears a bit to prostate cancer. Could you tell us about Abstract 5005 which is titled, “EMBARK Post Hoc Analysis of Impact of Treatment Suspension on Health Quality-of-Life?” Dr. Neeraj Agarwal: Of course, I'd be happy to. So, enzalutamide was recently granted FDA approval for the treatment of patients with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high-risk of metastasis, based on the results of the EMBARK trial, which was a phase 3 study where patients with high-risk biochemical recurrence were randomized to receive either enzalutamide with leuprolide, enzalutamide monotherapy, or placebo plus leuprolide. The primary endpoint was metastasis-free survival with secondary endpoints including overall survival and safety.  Results showed that patients receiving enzalutamide alone or enzalutamide plus leuprolide had significantly improved metastasis-free survival compared to those treated with leuprolide alone while preserving health-related quality-of-life.   One important aspect in the design of the trial was that patients who achieved undetectable PSA at week 37 underwent treatment suspension. The treatment was resumed if PSA rose to more than 2 ng/ml for patients who underwent radical proctectomy or when PSA rose to more than 5 ng/ml for those who did not undergo surgery.  In this abstract, Dr. Stephen Freedland and colleagues present a post-hoc analysis of health-related quality-of-life outcomes after treatment suspension between weeks 37 and 205. They found that treatment was suspended in 90.9% of patients receiving enzalutamide plus leuprolide, 85.9% of those receiving enzalutamide monotherapy, and 67.8% of those receiving leuprolide monotherapy. Among those patients who stayed on treatment suspension, a trend toward numerical improvement in health-related quality-of-life after week 37 was seen in all 3 arms and this reached clinically meaningful threshold at week 205 in pain questionnaires, physical well-being, urinary and bowel symptoms. For hormonal treatment side effects, all arms reached clinically meaningful improvement at the subsequent assessments of week 49 to week 97. However, patients slowly deteriorated, with clinically meaningful deterioration at week 205 relative to week 37 in patients receiving the combination of enzalutamide and leuprolide and those treated with leuprolide.    Concerning sexual activity, a clinically meaningful improvement was reported only in patients receiving enzalutamide plus leuprolide, possibly because sexual function was better preserved prior to suspension in the enzalutamide monotherapy arm and thus there was less opportunity for “improvement” while on suspension.  Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for this great summary. This analysis confirms that treatment suspension in good responders might lead to a clinically meaningful improvements in health-related quality-of-life.   Now, moving on to patients with metastatic castration-resistant prostate cancer, what can you tell us, about Abstract 5008 titled, “Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore”?  Dr. Neeraj Agarwal: Sure, Jeanny. The PSMAfore trial was a phase 3 study that compared the efficacy of 177Lu-PSMA-617 versus an ARPI switch in patients with mCRPC and prior progression on a first ARPI, and not previously exposed to docetaxel chemotherapy. The primary endpoint was rPFS and OS was an important secondary endpoint. The primary analysis presented at ESMO 2023 showed a significantly prolonged rPFS in patients receiving lutetium. In the abstract that will be featured at the 2024 ASCO Annual Meeting, Dr. Johann De Bono and colleagues present an exploratory analysis regarding the associations between baseline circulating tumor DNA and outcomes.  ctDNA fraction was evaluated in all samples as well as alterations in key prostate cancer drivers prevalent in more than 10% of participants.  The investigators sought to interrogate the association of ctDNA fraction or alterations with rPFS, PSA response, and RECIST response at data cutoff. They showed that median rPFS was significantly shorter in patients with a ctDNA fraction >1% compared to those with a fraction < 1% regardless of the treatment arm. Furthermore, ctDNA fraction >1% was also associated with worst RECIST response and PSA50 response. Regarding prostate cancer drivers, median rPFS was significantly shorter in patients with alterations in the AR, TP53 or PTEN in both treatment arms. There was no significant association between ctDNA alterations and PSA or objective responses. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that the presence of a ctDNA fraction >1% or alterations in AR, P53 and PTEN were all associated with worse outcomes regardless of treatment with lutetium or change in the ARPI. These data are definitely important for counseling and prognostication of patients in the clinic and may guide the design of future clinical trials. Let's move on to kidney cancer. Neeraj, do you have any updates for us?  Dr. Neeraj Agarwal:  Sure. In Abstract 4512 titled, “A Multi-institution Analysis of Outcomes with First-Line Therapy for 99 Patients with Metastatic Chromophobe Renal Cell Carcinoma,” Dr. Sahil Doshi and colleagues present a retrospective, multi-institutional study comparing survival outcomes, including time-to-treatment failure and overall survival, between different first-line treatment options in patients with metastatic chromophobe renal cell carcinoma, where limited clinical trial data exists to guide systemic therapy. They categorized patients into 4 treatment groups: and immune checkpoint inhibitors + targeted therapy doublets (such as ICI VEGF TKI); pure immune checkpoint inhibitor monotherapy and doublets (such as ipilimumab plus nivolumab); targeted therapy doublets (such as lenvatinib plus everolimus), and targeted monotherapy (such as sunitinib).  They identified 99 patients, of whom 54 patients received targeted monotherapy, 17 received ICI VEGF-TKI, 14 received targeted doublet, and 14 patients received only ICI therapies. So the patients treated with any doublet containing a targeted agent had a 52% decrease in the risk of treatment failure and a 44% decrease in the risk of death compared to those treated with targeted monotherapy. The median time to treatment failure was 15 months with IO-targeted doublet, and the median overall survival was 56 months. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that targeted doublet regimens resulted in a longer time to treatment failure and overall survival compared to any monotherapy in patients with chromophobe metastatic RCC and definitely provides valuable insights on treatment selection, albeit I would say there's still a small number of patients that were included in this retrospective analysis. Dr. Neeraj Agarwal: I completely agree this is a relatively small number of patients, but I decided to highlight the abstract given how rare the cancer is, and it is highly unlikely that we'll see large randomized clinical trials in patients with metastatic chromophobe renal cell carcinoma.  So, before we wrap up the podcast, what would you like to tell us about Abstract 5009 which is titled, “A Phase II Trial of Pembrolizumab Platinum Based Chemotherapy as First Line Systemic Therapy in Advanced Penile Cancer: HERCULES (LACOG 0218) Trial.” Dr. Jeanny Aragon-Ching: I'm glad you brought this up, Neeraj. As our listeners may know, advanced penile squamous cell carcinoma has a poor prognosis with limited treatment options. From this perspective, the results of the LACOG 0218 trial are very important. As you mentioned, this was a phase 2 single-arm study evaluating the addition of pembrolizumab to platinum-based chemotherapy as first-line treatment in patients with metastatic or locally advanced penile squamous cell carcinoma not amenable to curative therapy. Patients enrolled received chemotherapy, namely 5-Fluorouracil with cisplatin or carboplatin and pembrolizumab 200 mg IV every 3 weeks for 6 cycles, followed by pembrolizumab 200 mg IV every 3 weeks up to 34 cycles. The primary endpoint was confirmed overall response rate by investigator assessment.  In the 33 patients eligible for the efficacy analysis, the confirmed ORR by investigator assessment was 39.4% and included one complete response and 12 partial responses. The confirmed ORR was 75% in patients with high TMB and 55.6% in patients positive for HPV16, making TMB and HPV16 potential predictive biomarkers for efficacy in this study. Concerning the toxicity profile, any grade treatment-related adverse events were reported in around 92% of patients, and grade 3 or more treatment-related adverse events occurred in 51% of patients. 10.8% of patients discontinued treatment due to adverse events.  Dr. Neeraj Agarwal: Thank you, Jeanny. I would like to add that HERCULES is the first trial to demonstrate the efficacy of an immune checkpoint inhibitor in advanced penile squamous cell carcinoma with a manageable safety profile. Thus, the combination of ICI with platinum-based chemotherapy is a promising treatment for advanced penile squamous cell carcinoma and warrants further investigation.  Dr. Jeanny Aragon-Ching: I agree, Neeraj. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Jeanny, I really want to thank you for your participation and valuable insights. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. It was a pleasure.  Dr. Neeraj Agarwal:  As we bring this podcast to an end, I would like to acknowledge the significant advances happening in the treatment of patients with genitourinary cancers. During our upcoming 2024 ASCO Annual Meeting, there will be an array of different studies featuring practice-changing data presented by researchers and physicians from around the globe. I urge our listeners to not only participate in this event to celebrate these achievements, but to also play a role in sharing these cutting-edge data with healthcare professionals worldwide. Through our collective efforts, we can surely optimize the benefits of patients on a global scale.   And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you very much.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:  Dr. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:   @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:    Dr. Neeraj Agarwal:     Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:  Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

Second Episode of the new TMB series called "Weekend Hangover" where TMB host Dustin Coyner, and "Ricky" Bobby Leavitt discuss the past weekend's races. This past weekend MotoGP happened under the lights at Qatar, while MotoAmerica was running the Daytona 200. I'm sure there's lots of crap to talk about all sorts of subjects. Enjoy! Please Like/share/subscribe/comment all that stuff... ** Sign up for your next TrackDaz event here: http://www.trackdaz.com Next event is April 20-21 WEEKEND at Thunderhill's west track http://www.trackrabbit.com/s/2kmm *PIRELLI TIRES!! ** You can get your Pirelli rubber from us directly on our registration site. Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdaz Follow the TrackDaz Crew: @chili144 @jimmyz853 @phen2210 @gil823 @formula_r @chili144 @lgbrown_ @dkm60 @canea121 @g_offsims @ricardo.abueg @r6_krissy_ @trackdazkaren @fharo3 @modbaez @m39023 @dreek46 @bubblesrides

Dr. Shannon Westin and her guests, Dr. Herbert Duvivier and Dr. Richard Schilsky, discuss the paper “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study” published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth into articles published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. As always, it is my pleasure to serve and bring this information to you.  Today, we will be discussing, “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” And this was published in the JCO on August 10th, 2023.  None of the authors have any conflicts of interest to disclose.  Joining me today are two of the authors, Dr. Herbert Duvivier, the principal investigator of this arm of the TAPUR trial. Welcome. Dr. Herbert Duvivier: Thank you.  Shannon Westin: And then, of course, many of you know Dr. Richard Schilsky, who is the former CMO and Executive Vice President of ASCO and a principal investigator on the TAPUR study.   Dr. Richard Schilsky: Thank you, Shannon.  Shannon Westin: So, let's get going. I think the first thing would be great is to level set and make sure everyone knows exactly what this TAPUR basket trial is, the Targeted Agent and Profiling Utilization Registry study. Can you guys give the audience a brief description of the objective of TAPUR and maybe how it came to fruition?  Dr. Richard Schilsky: Sure. This is Richard Schilsky. Maybe I can start with that. The TAPUR study is a prospective, phase II, multi-basket, multi-center genomic-matching trial. Its primary objective is to identify signals of drug activity for targeted agents that are already marketed. But in the TAPUR study they are being used outside of their FDA-approved indication. The study, as you may know, was conceived in 2014, launched in 2016, and is still enrolling patients across the country. Really, the genesis of the study came from the fact that it began at the time where genomic profiling of patients with advanced cancer was becoming more commonplace. Genomic alterations that could be targeted by already marketed drugs were being identified. However, patients and doctors were having difficulty accessing these drugs because they were not used on label and were unlikely to be covered by insurance. And moreover, even if they could access the drugs, there was no organized mechanism to collect outcome data and report on the results of the patient experience receiving that treatment.  So those factors led to the development of TAPUR, which attempts to solve both the drug access problem by having collaborating pharmaceutical companies donate their drugs to the trial so they're available to patients at no cost, but also implements a structured data collection mechanism so all of the relevant clinical outcomes with the patients can be collected and ultimately reported. And that's how TAPUR came about. Shannon Westin: Well, it was so necessary, and I think we do so much of our oncology treatments off-label, but as we get more and more expensive drugs when we move away from chemotherapies and more targeted immunotherapies, it's very hard to get those drugs off label. So this was such a relevant and necessary trial that had to happen, and it's a great example of leadership that you had the vision to put this together through ASCO.  I think the natural next question for me is having not put patients on the TAPUR study, how does a patient join this study? How do they get started? Walk us through that. Dr. Herbert Duvivier: At our institution, normally, all the physicians are aware of the TAPUR trial through internal conversations. When they have patients who have been treated with multiple lines of standard therapy, usually the next step for them is to get NGS testing. We have a research team that reviews all NGS testing for these patients and knows the open arms of the TAPUR trial. And if there happens to be a particular patient who may match with one, they will inform the physician. It is then up to the physician to speak to the patient about that option.  Shannon Westin: Do you have people come looking for the TAPUR trial or are these generally more established patients? Dr. Herbert Duvivier: From my perspective, I think it is usually established patients. Shannon Westin: I think what I love about this trial, and I have spoken about this trial in lectures around baskets, it's such a pragmatic design making it as straightforward as possible to really implement across different centers, whether academic or community, or wherever they are. I guess one of the questions always around these targeted therapies is the molecular selection. How do you make sure that people are being appropriately molecularly selected and how do you decide which testing to utilize?  Dr. Richard Schilsky: As you pointed out, Dr. Westin, the goal of the study from the beginning was to have a very pragmatic design, in a sense to have this study attempt to replicate the way oncologists were deploying precision medicine in their practice. The study has broad eligibility criteria, it has minimum necessary data collection, it uses conventional clinical evaluations, there are no additional clinical evaluations required that are not part of routine clinical care. And it just makes it easy to embed the study into the clinical workflow. The study is based largely at community sites, about 85% of the 268 participating sites are located in smaller communities. The study has a set of genomic matching rules that are listed in the protocol and baked into the IT platform for the study as a rules engine. For every treatment available in TAPUR, there is a set of genomic inclusion and exclusion criteria.  So in essence the way it works, the physician determines that NGS testing is appropriate for their patient and can use any NGS test they want, as long as the test is performed in a CLIA certified, CAP, or New York State-accredited laboratory. They select the test, they select the biospecimen to be tested, they get the results, they look at the results, and they determine if there is a genomic alteration in the patient's tumor that is targeted by one of the study treatments in the TAPUR study. They can enter that into the rules engine, the rules engine will confirm or not that the appropriate alteration of treatment has been selected. If it is confirmed, then the patient can immediately be enrolled in the study if they meet the clinical inclusion and exclusion criteria.  If the rules engine does not confirm the treatment match is appropriate, or in some cases there are multiple possible treatment matches, if there are multiple alterations that can be targeted, or another case is the doctor is simply uncertain about which alteration is best to target, then the clinical site can send that patient case to the TAPUR molecular tumor board. A group of experts convenes weekly that reviews the clinical history, the pathology report, genomic test report, the prior therapy the patient has received, and they make a determination as to whether or not there is an appropriate therapy that's available on TAPUR for the patient. And if not, then are there other potential therapies  that are available that could be considered. That information is sent back to the treating physician who determines whether or not here she feels that treatment option is appropriate for their patient, and if so, the patient can then be enrolled and receive the therapy. Shannon Westin: So awesome. I love the idea. If we don't have an arm for you on our trial, we can help assist you potentially determine an option for your patient outside of that. That's so clever.  Okay. So let's get into this particular arm. Obviously, our audience is quite savvy and are aware of the role of immune checkpoint inhibition across a number of solid tumors. Could you describe what you sought to determine in this particular arm of the TAPUR study?  Dr. Herbert Duvivier: I think one of the most important things to remember about this study is that this study was opened and accruing prior to pembrolizumab becoming FDA approved in, I think, June of 2020. So prior to June of 2020, there was no indication for pembrolizumab in high TMB tumor types and the goal of the study was to determine if pembrolizumab had any overall response rate, duration of responses, progression-free survival, or overall survival advantage over what would be considered standard chemotherapy at that time in patients with high TMB. Dr. Richard Schilsky: Yeah, that's exactly right. And in this paper that we're discussing, we're reporting on two different groups of patients. So there's a group of 28 patients, all with colorectal cancer, all of whom had high tumor mutation burden, as defined by the protocol. And that's one group. Then there's a second, larger group of patients, which is a very heterogeneous group of solid tumor patients. And the reason that that group is reported is there were patients who were being enrolled with multiple different tumor types with high tumor mutation burden. Each tumor type determined a specific, tumor-specific cohort in the study, and they were enrolling at different rates depending upon how common the particular tumor type was. But once the FDA approval for pembrolizumab, for any tumor with a high tumor mutation burden, was granted, then all of those cohorts essentially had to close to new enrollments because there was no longer an off-label use for pembrolizumab in that setting - everything was now on the label.  The result was that we then basically collapsed all of the open cohorts that were not then going to be able to complete into this one large, heterogeneous cohort that's being reported in this paper. And going back to the colorectal results, in the paper, we describe a disease control rate of 31%, an objective response rate of 11%. There were three patients who had partial responses lasting 12, 27, and 97 weeks each. And I think it's important to point out that in this particular cohort, essentially all of the colon cancer patients were microsatellite stable. So that's an interesting nuance here because we know that pembrolizumab is active and has an FDA approval in microsatellite high tumors. But this particular group of patients was essentially all microsatellite stable, suggesting that even in that population, if the tumor also has a high tumor mutation burden, the patient has the potential to respond and benefit from the treatment. Shannon Westin: I found that very intriguing. And, of course, as a gynecologic oncologist that treats endometrial cancer, I'm always thinking about MSI and microsatellite stability. So I was very intrigued by this. We are not seeing a ton of TMB high in our population, but there are some patients that do have that.  So let's talk a little bit about the results for the collapsed all solid tumor group. What did you find there? Dr. Herbert Duvivier: In the histology pool cohort, there were 47 patients representing 21 different tumor types, with a median tumor mutational burden of approximately 13 mutations per megabase with a range of 9 to 228. 40 of 47 patients had MSS disease, microsatellite stable disease. 6 of the 47, MSS was not reported, and 1 case was ambiguous. The disease control rate was about 45%, and the objective response rate was 26%. There were 3 complete responses: 1 in bladder, 1 in parotid, and 1 in squamous cell carcinoma. 9 partial responses and 9 stable disease 16 plus weeks. Of interest in the patients that were responding, 10 out of the 21 patients had POLE or POLD1 mutations, and 9 of the 21 patients had BRCA1 or BRCA2 mutations, although most of those mutations were classified as variants of uncertain significance. Shannon Westin: That's really interesting. We've seen pretty good data for POLE and benefit from immunotherapy, although at least in the GYN tumors and especially in endometrial cancer, those patients usually do well no matter what you do with them. And so they don't often make it to get immunotherapy because they have a complete response up front to their surgeries. So very intriguing to see that driving benefit. I'm just interested to see because it seems like there's a range that you were quoting of what was considered to be TMB high. So did you see a correlation for response to therapy based on how high the tumor mutational burden was in a given tumor or tumor type? Dr. Herbert Duvivier: Yes, actually we did see a moderately negative correlation between maximum percent change from baseline in a tumor and increasing TMB, which indicated an association between a higher TMB and greater shrinkage of tumor lesions. Dr. Richard Schilsky: I should point out, by the way, that when we introduced this arm into the TAPUR study, this high tumor mutation burden arm, as Dr. Duvivier has already pointed out, it was prior to, of course, the FDA approval, and the FDA approval is for tumors that have at least 10 mutations per megabase. It was also prior to the adoption of that threshold of 10, based on work by Friends of Cancer Research and others as sort of the convention for what defined a high tumor mutation burden. So when we put this into TAPUR, we essentially consulted with some of the testing laboratories. We consulted with Merck, the sponsor for pembrolizumab and actually in the TAPUR study, we defined a threshold of 9 mutations per megabase as defining high tumor mutation burden.  Now, as Dr. Duvivier said, there's a broad range of tumor mutation burden represented in this population, and there does seem, if you look at, if the readers want to look at figure 4 in our paper, there does seem to be a general correlation between best response and number of mutations per megabase, which also holds true in a modest way for both progression-free and overall survival. So, TMB is somewhat predictive of favorable outcomes. It's not a perfect biomarker by any means, but generally speaking, if you have enough patients, you can define this sort of trend to support the notion that the more mutations, the greater the likelihood of benefit. Shannon Westin: That makes a lot of sense. One other thing that I just wanted to comment on before we kind of bring the podcast to a close is I was really struck by the high proportion of underrepresented minorities in this arm of TAPUR, and I just would love to hear your thoughts on how the design improves recruiting in this population of patients. Dr. Richard Schilsky: This was a goal of the study, very intentional. When you look at the overall study demographics, there are about 2800 patients now that have been enrolled on TAPUR overall. Almost 12% are black, about 6% are Hispanic, about 4% Asian. The median age is about 64. So it's a slightly older population. The goal always was to enroll a population of patients in TAPUR that was broadly representative of the patients that oncologists treat in practice. In the way we accomplished what we've accomplished, we still have work we can do to improve it. But the clinical sites were carefully selected and vetted. We focused on sites that served a significant fraction of minority patients. We made the eligibility criteria simple and broad, so many of the eligibility criteria that might typically exclude minority populations or older patients from clinical trials are not exclusion criteria in TAPUR. We made the operations of the trial simple, so patients really aren't asked to do much more than what they would normally be asked to do in the course of their routine cancer care. So I think all of those things together have made it possible to attract and enroll a more representative patient population in the study. And we're very gratified by that because when you look at many of the registration trials for many cancer drugs, minorities and older people are terribly underrepresented. So we feel that TAPUR is adding value there and adding useful information. Shannon Westin: I think it's so generalizable and really the way people are practicing, and so to see similar results or concordant results, despite not as much of the rigorous testing and potentially exclusion of certain patient populations is really reassuring and certainly very exciting.  The last question is what's coming next? What other arms are coming soon? And can sites still join? Is this something where it's ongoing enrollment and participation? Dr. Richard Schilsky: So sites can still join. There's a place on the ASCO website where sites can find more information about TAPUR, and there's essentially a form available where sites can indicate their interest in joining the study. And then those sites are then evaluated by the TAPUR study team to determine if they meet the minimum necessary requirements to qualify to join the study. There's a lot more data coming out, many more papers that are in press and being written. There are two abstracts that will be presented in April at the AACR meeting. There are three abstracts that have been submitted for the ASCO annual meeting. So a lot more data to come.  This is a study that, at least hypothetically, could continue in perpetuity as long as we're able to continue to attract new drugs and new treatment combinations onto the TAPUR study platform. So the TAPUR team is always on the lookout for drugs that are about to get an FDA approval and that could be appropriate for the TAPUR study and continue to talk to many pharmaceutical companies about their interest in potentially putting their drugs on the platform. Shannon Westin: Well, great. Thank you both for taking the time. I know you're both incredibly busy.  Again, this has been “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” I'm your host, Shannon Westin, and I'm so grateful that you joined us on JCO After Hours. Please check out our other offerings on the website or wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Duvivier's COIs: Speakers' Bureau Company name: Guardant Health Company name: AstraZeneca Company name: Regeneron  Schilsky's COIs: Leadership Company name: Clarified Precision Medicine Company name: Leap Therapeutics Stock and Other Ownership Interests Company name: EQRx Company name: Leap Therapeutics Consulting or Advisory Role Company name: Cellworks Company name: Scandion Oncology Company name: Bryologyx Company name: Illumina Company name: EQRx Company name: Syapse Company name: Zephyr AI Company name: AADi Research Funding Company name: AstraZeneca Company name: Bayer Company name: Bristol-Myers Squibb Company name: Genentech/Roche Company name: Lilly Company name: Merck  

In this episode, we welcome Emmy-nominated Composer, Score Producer and Musician Chris Ruggiero. Chris has worked on films such as Emily the Criminal, Swallow, The Martha Mitchell Effect, Minding the Gap, Hooligan Sparrow, “Soundbreaking: Stories from the Cutting Edge of Recorded Music,” One Child Nation, Plan C, Camp Courage, episodes of “American Masters" and “American Experience” — and Resynator, which is premiering at SXSW this month. In our chat, we hear Chris' backstory, his path from working at MTV, to creating jingles for brands, on through scoring many of today's top independent films and documentaries. The Making Of is presented by AJA Video Systems.Versatile color management and conversion with AJA ColorBox From film to live production, color is an art. Achieving the right look requires a combination of talent and access to tools like AJA ColorBox. 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Clarke created this cinematic masterpiece. Author Michael Benson explains how 2001 was made, telling the story primarily through the two people most responsible for the film, Kubrick and science fiction legend Arthur C. Clarke. Benson interviewed Clarke many times, and has also spoken at length with Kubrick's widow, Christiane; with visual effects supervisor Doug Trumbull; with Dan Richter, who played 2001's leading man-ape; and many others.A colorful nonfiction narrative packed with memorable characters and remarkable incidents, Space Odyssey provides a 360-degree view of this extraordinary work, tracking the film from Kubrick and Clarke's first meeting in New York in 1964 through its UK production from 1965-1968, during which some of the most complex sets ever made were merged with visual effects so innovative that they scarcely seem dated today. A concluding chapter examines the film's legacy as it grew into it current justifiably exalted status. 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Event:Cinelease Open HouseCinelease, known for providing the industry's most extensive array of grip, electrical and lighting equipment and full-service studios, opens its doors for a day of talks, tech, live music, games, food truck favorites, drafts & sodas, and out of this world presentations. The festivities run from noon to 8pm on March 16, 2024 at Cinelease headquarters in Los Angeles.Cinelease has lined up something for everyone at their let-your-hair-down Open House: Cutting-edge tech from AC Lighting, ACT (AC Power), Aputure, ARRI, Camera Car, Creamsource, Elation, Illumination Dynamics, INDU, InnerCircle, Jagoteq, JL Fisher, K5600, Kino Flo, KOTO, LA North Studios, LiteGear, Leitz, Lightscape, LRX, Maccam, Matthews Studio Equipment, NBCUniversal / Cineo, Nanlux, Osram, Power Gems, Roe Visuals, Rosco, RST Visions in Color, Sony, Sumolight, TRP, RT Pro, TMB and more. Learn more hereFeatured NYC Event: Cine Gear NY | March 14-16, 2024Mark your calendars for March and head on out to the thriving Industry City complex along the Brooklyn Upper Bay waterside. Cine Gear's studio-style event is gathering steam as state-of–the-art technology brands are preparing to reveal their latest & greatest gear in the historic Paper Factory Hall. New this year is Photo Focus, a one-day educational event dedicated to the art and craft of Still Photography.Get your Free Passes herePodcast Rewind:Feb. 2024 - Ep. 26…The Making Of is published by Michael Valinsky.If you'd like to promote your company to over 11,500 leading film & TV pros reading this newsletter, please email us at: mvalinsky@me.com Get full access to The Making Of at themakingof.substack.com/subscribe

New TMB series called "Weekend Hangover" where TMB host Dustin Coyner, and "Ricky" Bobby Leavitt discuss the past weekend's races. This past weekend was the season opener of World SBK. We'll discuss everything SBK, which riders surprised people, which ones disappointed, drama in the races, etc.. Also we'll touch a bit on the World SS races, and even the Australian SBK races which were taking place that same weekend. Enjoy! It was fun chatting with these goons, hope you enjoy. Next TrackDaz events March 1 at Buttonwillow with the Attack Yamaha boys Next event is: Friday, March 1st Sign up here: https://tinyurl.com/AttackYamahaMarch1 March 23-24 at Thunderhill West Track. Sign up here: https://tinyurl.com/MarchTHillWest Please Like/share/subscribe/comment all that stuff... ** Sign up for your next TrackDaz event here: http://www.trackdaz.com **PIRELLI TIRES!! *** You can get your Pirelli rubber from us directly on our registration site. Follow us on Facebook: / trackdaz Follow us on Instagram: @trackdaz Follow the TrackDaz Crew: @chili144 @jimmyz853 @phen2210 @gil823 @formula_r @chili144 @lgbrown_ @dkm60 @canea121 @g_offsims @ricardo.abueg @trackdazkaren @fharo3 @modbaez @m39023 @dreek46 @bubblesrides

In today's episode of Backpacker Radio presented by The Trek, we are once again loving love. That's right, it's the 4th edition of our Valentine's Day-themed show. Today we catch up with Wesley and Marie Black, known on trail as Yeti Legs and Basecamp. Less than two years after meeting, they were not only married but together taking on a thru-hike of the PCT. Wesley and Marie pull no punches in sharing the nitty-gritty of making a relationship work during a thru-hike and are especially candid about their on-trail sex life including their hygiene practices, foreplay, what they use for lubrication, best positions in a tent, and more. This one is entertaining, enlightening, and slightly erotic. Strap in. We wrap the show with what we would do if we could be our significant other for a day, the triple crown of petty fights we have with our partners, Marie shares a plastic melting shit story, and Chaunce has a very dumb stupid thing of the week. Ka'Chava: Get 10% off at kachava.com/backpacker. Gossamer Gear: Use code “DINGLEBERRY” for 20% off packs at gossamergear.com.  [divider] Interview with Wes & Marie Wes & Marie's Instagram Wes & Marie's Linktree Time stamps & Questions 00:04:55 - Reminders: Last call to apply for the BPR internship, Tyvek wall goes on sale next week, and the Badger Sponsorship launched today! 00:09:35 - Introducing Wes & Marie 00:11:40 - Story of how Wes & Marie met 00:14:30 - When did you get engaged? 00:19:42 - Did you have any concerns about getting engaged so quickly? 00:24:00 - Did you have any doubts in the first six months? 00:26:01 - Do you have baby fever? 00:28:53 - What led to deciding to thru-hike together? 00:32:05 - What outdoor experience did you have before meeting each other? 00:35:30 - How did you transition from running to hiking? 00:38:16 - When did you realize you had a lot of heavy gear? 00:40:30 - What was it like hiking in a high snow year? 00:43:28 - How did your mileage change between the desert and the Sierras? 00:44:50 - What did you learn about each other on the PCT you didn't know before? 00:50:40 - How did you handle the time stress? 00:56:20 - Tell us about your career in film 01:01:25 - What were your best fights on trail? 01:13:20 - What other tips do you have for couples on trail? 01:15:12 - What's your sex life like on trail? 01:18:32 - What are your tips for having great sex on trail? 01:24:27 - Did you bring any toys? 01:26:00 - Why didn't you have sex during the day? 01:27:23 - Did you take any of your PCT lessons into the Tour du Mont Blanc or the CT? 01:29:24 - Raise the shoe game! 01:47:44 - Tell us about the Colorado Trail hike 01:52:50 - Fuck Marry Kill: PCT, TMB, CT 01:54:40 - Will you share one of your favorite hidden gem hikes? 01:56:11 - Tell us about your podcast 01:58:35 - Tell us about how you met Dirt Diva Segments Trek Propaganda: The Ultimate Guide to Thru-Hiking Electronics by Alex “GPS” Brown QOTD: If you could wake up and be your significant other for a day, what would you do that day? Stupid Thing of the Week Triple Crown of petty fights you have with your partner Gross or Not Gross Mail Bag 5 Star Review [divider] Check out our sound guy @paulyboyshallcross. Leave us a voicemail! Subscribe to this podcast on iTunes (and please leave us a review)!  Find us on Spotify, Stitcher, and Google Play. Support us on Patreon to get bonus content. Advertise on Backpacker Radio Follow The Trek, Chaunce, Badger, and Trail Correspondents on Instagram. Follow Backpacker Radio, The Trek and Chaunce on YouTube. Follow Backpacker Radio on Tik Tok.  Our theme song is Walking Slow by Animal Years. A super big thank you to our Chuck Norris Award winner(s) from Patreon: Alex & Misty with Navigators Crafting, Andrew, Austen McDaniel, Austin Ford, Brad & Blair (Thirteen Adventures), Brent Stenberg, Bryan Alsop, Christopher Marshburn, Coach from Marion Outdoors, Dayne, Derek Koch, Eric Casper, Erik Hofmann, Greg Knight, Greg McDaniel may he bring honor to his name, Ironhike endurance productions, Jason “Snail” Snailer, Liz Seger, Patrick Cianciolo, Sawyer Products, SPAM, Timothy Hahn, and Tracy “Trigger” Fawns. A big thank you to our Cinnamon Connection Champions from Patreon: 12 Trees Farms, Dcnerdlet, Emily Galusha, Hailey Buckingham, Jeanie, Jeanne Latshaw, Jeff LaFranier, Joann Menzer, Keith Dobie Jr, Peter, and Ruth S.

The Texas Medical Board clarifies new fingerprinting requirement ahead of February license renewals. Get instructions and details at the TMB website. Read the TMT article at www.texmed.org/TMT.

JCO PO author Dr. Amit Mahipal shares insights into his JCO PO article, “Tumor Mutational Burden in Real-world Patients with Pancreatic Cancer: Genomic Alterations and Predictive Value for Immune Checkpoint Inhibitor Effectiveness.” Host Dr. Rafeh Naqash and Dr Mahipal discuss real world evidence of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma. TRANSCRIPT Dr. Rafeh Naqash: Welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center, University of Oklahoma. Today we are joined by Dr. Amit Mahipal, Professor of Medicine and Director of GI Oncology at the Case Western Reserve University in Seidman Cancer Center. Dr. Mahipal is also the author of the JCO Precision Oncology article titled "Tumor Mutational Burden in Real World Patients with Pancreatic Cancer: Genomic Alterations and Predictive Value of Immune Checkpoint Inhibitor Effectiveness."  Our guest disclosures will be linked in the transcript. For the sake of this conversation, we will refer to each other using our first names. So Amit, welcome to our podcast and thank you for joining us today. Dr. Amit Mahipal: Thanks for having me here. Dr. Rafeh Naqash: Excellent. We came across your article in JCO Precision Oncology and it really aroused my interest because the topic and the audience that it caters to is very important in the current times. Because immunotherapy generally is considered- pancreas cancer the graveyard in immunotherapy in essence, based on what I have seen or what I have encountered. And now you're the expert here who sees people with pancreas cancer or has done a lot of work in pancreas cancer research side. So can you tell us the context of this work and why you wanted to look at immune checkpoint inhibitors in pancreas cancer? Dr. Amit Mahipal: Absolutely, Rafeh. As you mentioned, pancreatic cancer is considered a what we call "cold tumors." They don't typically respond to immunotherapy. And when we talk to our patients or patient advocates, as you know, patients are very excited about immunotherapy. Immunotherapy has transformed the treatment for a lot of different cancers and not only has increased survival, but the quality of life is so much different than with chemotherapy. This work came from based on the KEYNOTE-158 trial, which was a tumor-agnostic trial which accrued patients who had TMB high tumor. What that means is that tumor mutation had more than 10 mutations per megabase. And what happens is because of that trial, more than 200 patient trial, the FDA actually approved this immunotherapy or pembrolizumab as a single agent pembrolizumab for any patient with a solid tumor who has high TMB. Again, tumor mutation burden, more than 10 mut/Mb. This question comes in now. Does this apply to our pancreatic cancer patient groups? Especially as we know these are "cold tumors" that typically do not respond. There have been multiple trials looking at immunotherapy, single agent, dual immunotherapy agents, as well as combinations with chemotherapy, with somewhat very, very limited success. So that was kind of the basis. So we wanted to look at this retrospective kind of review of a big database to see how many patients we can find who have high TMB and see in that patient population is immunotherapy really active based on the FDA approval or is pancreatic cancer not a tumor where we should try immunotherapy unit as a selective group.    Dr. Rafeh Naqash: Thank you for that explanation. Taking a step back again, since you see these individuals with pancreatic cancer I imagine day in and day out in the space of drug development, what is the general current standard of care approach for individuals with pancreas cancer in your clinic? I'm talking about what are the most common approaches that you utilize that seem to be working or have FDA approvals in the pancreas cancer space. Dr. Amit Mahipal: As with any tumor, the first thing is obviously staging. So depending on whether we're dealing with early stage or advanced stage and what are the goals of treatment. At this point, the only thing that can cure pancreatic cancer patients that would be considered conventional therapy is surgical resection. So any patient who is a candidate for surgical resection is in a different bucket compared to advanced patients. For early stage patients, we try to do what we call neoadjuvant treatment or neoadjuvant chemotherapy. We shrink the tumor or at least maintain it, look at the biology of the disease, and then take them to surgery, which typically involves a Whipple procedure if it's a head of the pancreatic mass.   Moving on to advanced patients, that's where we know the goal of treatment is palliative to increase survival, but unfortunately, most of the times we cannot cure them. And there the standard of care options include systemic chemotherapy. We have two typical regimens that we use, one is called FOLFIRINOX, which is a three-drug regimen of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan. And another regimen is gemcitabine plus abraxane, which is a two-drug regimen of gemcitabine plus abraxane. These are considered the standard of care. Unfortunately, the median survival even with the best standard of care chemotherapy is only about a year, 12-13 months, depending on what trials we look at.  Dr. Rafeh Naqash: I still remember some of these regimens from my fellowship, where we had to decide which to give to each individual based on their performance status and clinical status, etc. But now I can see a lot of ongoing drug development in the space of pancreas cancer. I'm guessing that's why you wanted to assess both the molecular genomic landscape of pancreas cancer in this study and also look at the immune biomarker aspect. Could you tell us a little bit about the Foundation Medicine Clinical Genomic Database? How did you identify the patients, how many patients did you identify, what you narrowed down in the criteria, and the eventual sample size of what you were looking at?  Dr. Amit Mahipal: FoundationOne has a rich database. They have two or three things. One is a genomic database only. So in our clinical practice, I think it's some sort of next-generation sequencing or mutational testing for all patients with advanced solid tumors. All of these goes into their database. All of the samples that are sent to FoundationOne that goes into their database where they know the diagnosis of the patient and the know the sequencing results of these patients. In addition, they also have a clinical database called Flatiron. Basically, they collaborated with them. Flatiron has about 280 or so cancer clinics throughout the country, so a lot of community settings and some academic sites as well. They did not only have a genomic database, but they actually have a clinical database. They have demographics, clinical features, baseline clinical features, comorbidities, what kind of treatment they received, what would be the stage of the cancer, how many months of treatment they received, and their overall survival, and so on. So from that perspective, the FoundationOne has access to this partnership with Flatiron, clinical genomic database where they have both clinical data as well as genomic database for a lot of these patients.  In our study, we only focused on patients with advanced pancreatic cancer. We excluded a lot of patients who did not have sequencing results available, they cannot be performed due to lack of tissue. So the first we talked about the genomic database and we found about about 21,932 patients, so almost 22,000 patients and there we had the sequencing and we also had the data on TMB or tumor mutational burden. So here, we classified them into two groups: high TMB and low TMB. High TMB was seen in 1.3% of the patients, and about 98.3% of the patients had low TMB. Here we looked at the genomic alterations between the two groups. So these are like our genomic group, so to speak of about 22,000 patients. And among them, as mentioned, that the clinical data was available for about 3300 patients or 3279 patients to be exact.   After excluding some of those patients, we found about 51 patients who received immunotherapy. And when we say immunotherapy, it is single agent immuno checkpoint inhibitor like pembrolizumab or nivolumab. And then we classified them into high TMB versus low TMB and then we also looked at patients with high TMB and compared them to who received immunotherapy versus other therapies. Just to recap, we had about 22,000 patients where we have the genomic database and about 3300 or so patients who we have both genomic and clinical data for this patients. One of the key findings was that high TMB was present in only 1.3% of the patients, or about 293 patients out of 21,932.  Dr. Rafeh Naqash: Definitely an interesting sample size that you had utilizing this resource, which, of course, is more or less real-world. It is important to gather real-world outcomes that you did.   So, going to the TMB story of this paper, where you looked at immune checkpoint inhibitor use in these individuals, was there a reason why some of the individuals with low TMB were also given immune checkpoint inhibitors? From my understanding, I did see some checkpoint inhibitor use there. What could be the explanation for that? Dr. Amit Mahipal: So this data is from 2014 to 2022. So from the span of about eight or so years. And as you know, immune checkpoint inhibitors were approved in the last decade. And there were a lot of not only trials, but even in the non-trial setting, people had tried immune checkpoint inhibitors in, frankly, different tumor types because of the success in some of the common tumor types, like melanomas, lung cancer, and so on. So I agree, as of today, we probably would not use immune checkpoint inhibitors in patients with low TMB or MSS. But at that time, I think that information was not available. So people with low TMB and MSI-stable tumors also received immune checkpoint inhibitors. But those numbers are again low. So it's not very high numbers. Dr. Rafeh Naqash: Understandable. That makes it a little more clear.  Now, you looked at the TMB aspect. I'm guessing you also looked at the MSI aspect of PDAC. What is your understanding, or what was your understanding before this study, and how did it enhance your understanding of the MSI aspect of PDAC? And I'm again guessing, since TMB high individuals are on the lower side percentage, so MSI high is likely to be low as well. Did you see any interaction between those MSI highs and the TMB highs on the PDAC side?  Dr. Amit Mahipal: Yeah, absolutely. So we are very excited in general about MSI-high tumors for solid tumors because of their response to immunotherapy. Although I would do a caveat because we still don't know how MSI-high pancreatic cancer responds although there have been some real-world, very, very small series as well. In this study, one of the things is, is high TMB totally driven by MSI-high? That's a question that comes up, and TMB high may not matter. It's only the MSI-high that might matter. So definitely when we look at this patient population, we found that the patients who were 35-36% of patients who were TMB high also had MSI-high patients. So we do expect MSI-high patients to have a higher TMB compared to MSS patients. But there were about 66 or two-thirds of the patients who did not have MSI-high tumors and still had high TMB, as defined by, again, ten mutations per megabase. So we did see patients with MSI-stable tumors who had high TMB. And I think that was one of our biggest questions. I think MSI-high patients, we all tend to think that we would try immunotherapy even if it's in pancreatic cancer. I think what is not clear, at least from the real-world or any of the trial data, is if we were to give MSI-stable patients who have high TMB, if we give immunotherapy, are there any responses or any disease control that we see? And that was one of the reasons for this study.  Dr. Rafeh Naqash: Now, one of the things that comes to mind, and again, I think you based it on the FDA approval for TMB high, which is ten mutations per megabase, as you defined earlier. I do a lot of biomarker research, and oftentimes you come across this aspect of binary versus a linear biomarker, in this case being TMB, where about ten, less than ten. Do you think, in general, an approach where you maybe have tertiles or quartiles or a biomarker, or perhaps a better approach in trying to stratify individuals who may or may not benefit from immunotherapy? Dr. Amit Mahipal: That's a great point. I think when we use ten mutations per megabase as a biomarker, as a binary endpoint, do we apply it to all tumor types? I don't think that's a fair comparison, frankly speaking. We do know that high TMB, even in different tumor types, do tend to respond a little bit better to or do have better outcomes for patients treated with immune checkpoint inhibitors in different tumor types. But what that cutoff is not known in most of the tumor types. And also, one of the problems is how do you measure TMB and is it standard across different platforms? Like I'm just giving some names like FoundationOne, Tempus, Caris, and some obviously like MSKCC and some other university-owned panels as well. And frankly, I think if you look at different panels and if you send the same tumor tissue, you will get different measurements. So I think standardization is a problem as well.  In one of the studies involving cholangiocarcinoma, for example, we found that a TMB of 5 was enough to have an additive effect of immunotherapy, same with chemotherapy, so to speak. But again, this needs to be validated.  So you're absolutely correct. I don't know why we use the binary endpoint, but on the same token, the binary endpoint is easy to understand as a clinician. Like, “Hey, someone has this, do this, not this.” And when we look into a continuous range, I think the benefit obviously varies between high and low, different tertiles, and becomes somewhat challenging. How do you classify patients and what treatments to give? So I think in clinical decision-making, we like the cutoffs, but I think in reality, I don't know if the cutoff is a true representation. And maybe with the more use of AI or computing, we can just input some values, and then it can tell us what the best treatment option might be for the patient. But that's way in the future. Dr. Rafeh Naqash: That would definitely be the futuristic approach of incorporating AI, machine learning perhaps, or even digital pathology slides in these individuals to ascertain which individuals benefit.  Going back to your paper, could you highlight some of the most important results that you identified as far as which individual is better, whether it was immunotherapy, and you've also looked at some of the mutation co-mutation status. Could you highlight that for our listeners? Dr. Amit Mahipal: So the first thing we looked at was the genomic database of almost 22,000 patients, and then we classified them into high TMB and low TMB, with about 300 patients in the high TMB group and the rest in the low TMB group. And what we found was, talking about again in the genomic database, that patients who have high TMB actually have low KRAS mutation. So if we think about KRAS mutation, pancreatic cancer, almost 85% or so of patients have KRAS mutation who have pancreatic adenocarcinoma. So patients in this subgroup, so in the high TMB group, only about two-thirds of the patients had KRAS mutation, compared to 92% of the patients with low TMB who had KRAS mutation. So just giving that perspective. So KRAS mutation, which is the most common mutation in pancreatic cancer and is a driver mutation, their rates vary differ from the high TMB group versus the low TMB group.   And then in addition, in the high TMB group, we found higher rates of BRCA mutation, BRAF mutation, interestingly, and then obviously from the DNA damage repair genes like PALB2 mutation, MSH2 or MSH6, MLH1, and PMS2. So all these mismatch repair protein mutations were higher. As I mentioned before, one-third of the patients with high TMB also had MSI-high. So it's not a totally unexpected finding. I think the biggest finding was that we found more KRAS wild-type pancreatic adenocarcinoma in the high TMB group, almost a third. And those tend to have different targetable mutations like BRCA2, BRAF, and PALB2 mutations. So I think one of the interesting findings is that patients in the high TMB group actually tend to have KRAS wild-type or less KRAS mutations. So they're not necessarily KRAS-driven tumors, and they have a higher chance of having other targetable mutations like BRAF and so on, for which we have therapies for. So it's always something to keep in mind. Dr. Rafeh Naqash: Would you think that from a DDR perspective, the mutations that you did  identify that were more prevalent in individuals with high TMB, do you think that this is linked to perhaps more DNA damage, more replication stress, more neoantigens leaning toward more tumor mutation burden perhaps? Or is there a different explanation?  Dr. Amit Mahipal: For sure. As we said, MSI-high tumors have mutations in the DNA damage repair pathway and they definitely tend to have higher TMB. So I don't think that is very surprising that we found PALB2, or other MMR genes like MSH2, MSH6, MLH1, and PMS2 at much higher rates. I think the interesting finding is the fact that the KRAS wild-type and having BRAF alterations at least that's not suspected to definitely increase TMB. Although if we look at colorectal cancer, BRAF mutation and MSI are somewhat correlated to patients with BRAF mutations and to have high rates of MSI-high tumors. But that's not the case in pancreatic cancer. We also found an increase in BRCA2 mutations as well. So I agree that the DNA damage pathway repair gene alteration is not unexpected because they tend to increase TMB, but I think the other mutations were interesting. Dr. Rafeh Naqash: And I think one other aspect of this, which I'm pretty sure you would've thought about is the germline implications for some of these mutations where you could very well end up screening not only the individual patient, but also their family members and have measures in place that we're trying to enhance screening opportunities there. In your current practice, you are at an academic center but I'm talking about in general with your experience, how common is it to sequence broad sequencing panels in individuals with pancreas cancer? The reason I asked that is I do a lot with lung cancer and even now despite having all those targets in lung cancer which sort of paved the pathway for targeted therapy in many tumor types, we still don't see a full uptake for NGS Phase I drug development. And I get a lot of referrals from outside and I often see that it's a limited gene panel. So what is your experience with pancreatic cancer? Dr. Amit Mahipal: We kind of changed our practice. Similar to you, I'm involved in drug developments. I've been a big proponent of NGS for almost a decade now, when didn't even have targeted therapies but these companies first came in and they're like, “Okay. We're very very low chance.” But now obviously, we transformed the treatment for a lot of different cancers. Especially lung cancer, you don't sometimes even start treatment before you get an NGS panel like you said in situ. So what we're finding, at least for pancreatic cancer, as you know, the targetable mutations are there but they are somewhat not that common, I would say, in the 10-15% range. So many people would get dissuaded and then it's like, what's the point of doing it?   But I think for those 10% to 15% of the patients, firstly we can really change their treatment course and their prognosis. Secondly, if you don't do it and they cannot go in a different clinical trials, now we have trials targeting KRAS G12C, but not only that, KRAS G12D which is the most common mutation we see in pancreatic cancer and so on. So it's becoming very very important. One thing, at least with our practice we adopted last two or three years is sending liquid biopsies or liquid based NGS or blood-based NGS testing. Otherwise, what's happening I would send a solid tumor NGS from the tissue. And pancreatic cancer as you know has sometimes a very small amount of tissue obtained from FNA. And inevitably after four weeks, we'll get the result that there's not enough tumor to do NGS testing. And then the patient comes one or two months later and then we order the test, and that just delays everything.  So now we adopted a practice where we are trying to send both blood based NGS and solid tumor NGS at the same time the first time of diagnosis when we see the oncologist for the first time. And that has really increased the rate of NGS testing results for our patient population. And it's not 100%, even in blood-based NGS, sometimes they may not be able to find enough circulating tumor cells to do this blood-based NGS testing, but at least they're having these. But you're correct. I think we still see about one third of the patients who had not had NGS testing or referred for phase I clinical trial and have gone through more than two or three line of therapies which is unfortunate for our patients.  Dr. Rafeh Naqash: That's a very interesting perspective on how important it is to sequence these individuals. As you said, it may not be that all of them may benefit, but the ones that have those important alterations, especially BRCA, PALB, and KRAS could benefit from novel precision medicine-based approaches.  A question that came to my mind, I saw that you were trying to look at MYC and turmeric low tumors as well. So what is the role of MYC in the context of these individuals? Is there any drug development that's going on? Because I see small cell lung cancer. MYC is an important target there. These are two different tumors, but it looks like there was a hint of some correlation with respect to some of the findings that you showed. Is that something that you're currently looking at or planning to look at?  Dr. Amit Mahipal: I think that if we just talk about MYC in general, it is present at somewhat lower rate. I think we found MYC amplification in about 5% or so of TMB-low patients who had that and not really seen in the TMB-high patients. So right now, I am not aware of any trials targeting MYC in pancreatic cancer. But as you said, if it's successful in lung cancer, maybe that's when we can transform into the pancreatic cancer group. Dr. Rafeh Naqash: Of course we can all learn from each other's specialties.We learned a lot from melanoma with respect to therapy. Hopefully, other fields can also benefit from each other's experiences in the space of drug development.  Thank you so much for this interesting discussion. The last few questions are more or less about you as an individual researcher. So could you tell us briefly on your career trajectory and what led you into the space of GI oncology, pancreas cancer, even for that matter, drug development? And some of the advice that you may want to give to listeners who are trainees or early career individuals? Dr. Amit Mahipal: Sure. So I have gone through some different institutions. During my fellowship, that's when I really decided that I wanted to do GI oncology. Prior to that, I actually have a Masters in Public Health, where I learned about epidemiological research and how to design clinical trials, how to design cohort studies. My focus was on, actually there was somewhat a lot, but one of my mentors was working on colorectal cancer, and they had this huge database called the Iowa Women's Health Study Database of 100,000 patients. So that's where I started by clearly getting into colorectal cancer and GI cancer in general and how to learn from this database, how to mine these databases, how to do analyses, which seems easy but is actually quite complicated.  During my fellowship, I think the key to it is finding a good mentor during the fellowship. And I worked with one of the top GI oncologists in the country who's practicing. And I worked under her and learned a lot not only from the clinic side but also from the research perspective and how sometimes you'll come up with the ideas during the clinic itself.Like, “Hey, this patient had this and why aren't we looking into this.” And she would even do some of the therapies based on phase II trials and she was a part of a lot of these trials and learning from those experiences.  And following my fellowship, I joined Moffitt Cancer Center, where I led the phase I program there. So I was heavily involved in drug development programs, all training programs I've been to, NIH in Bethesda, an observership in the CTEP program, and also did the ASCO/AACR Vail workshop, where you really learned a lot in just like one week. So those are kind of opportunities present for fellows and even the early investigators and attendings as well in the first few years can go there, have your proposal. And really they are the world experts in trial design and they'll talk about how to design trials, how to add collaborators, improve your trial, and basically learn the whole protocol in a week so to speak.   And then I was at Moffitt Cancer Center for about five, six years. My home was GI so I did both GI oncology as well as phase I. And in terms of the GI oncology, my main focus was pancreatic cancer and liver tumors. Then I was at Mayo Clinic in Rochester for about seven or so years. I kind of did the same thing and solidified my career at GI oncology, looking at liver tumors, and pancreatic cancer and then being a part of the phase I division program. And now, most recently, about a year or so ago, I joined Case Western to lead the GI program here. Dr. Rafeh Naqash: Are the winters in Cleveland better than the winters in Minnesota? Dr. Amit Mahipal: For sure. I always say, you don't know cold until you go to Minnesota. It's a different kind of cold. I'm sure people in Dakota might say the same thing, but the cold in Minnesota is very brutal and different compared to any other place I've been to.  Dr. Rafeh Naqash: Well, it was great learning about you. Thank you so much for spending this time with us and for sharing your work with our journal. We hope you'll continue to do the same in the near future.  Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ascopubs.org/podcasts. Dr. Amit Mahipal: Thank you for having me here, Rafeh. Good luck. Take care. Dr. Rafeh Naqash: Thank you so much. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   The guests on this podcast express their own opinions, experiences, and conclusions. Their statements do not necessarily express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Dr. Mahipal: Consulting or Advisory Role:QED TherapeuticsAstraZeneca/MedImmuneTaiho Oncology Speakers' Bureau:AstraZeneca Research Funding:Taiho Pharmaceutical"

Bienvenidos a un nuevo episodio de #NaturalmenteSascha Este es uno de los episodios más solicitados: ¡hablamos sobre la pérdida de grasa! Después de unas festividades donde podemos tener desorden en la alimentación y hacer menos ejercicio, sé que muchos están listos para retomar un estilo de vida más saludable. La pérdida de grasa es un proceso que requiere paciencia y un plan adaptado a cada uno En este episodio, comparto una fórmula específica que te ayudará a calcular un número de calorías en mantenimiento utilizando la Fórmula de Harris-Benedict. Además, te explico cómo ajustar este valor según tu nivel de actividad. Fórmula de Harris-Benedict: - Para hombres: TMB = 88.362 + (13.397 x peso en kg) + (4.799 x altura en cm) - (5.677 x edad en años) - Para mujeres: TMB = 447.593 + (9.247 x peso en kg) + (3.098 x altura en cm) - (4.330 x edad en años) Una vez que obtengas tu TMB (Tasa Metabólica Basal), puedes multiplicarlo por un factor de actividad para determinar las calorías en mantenimiento. Por ejemplo: - Sedentario (poco o ningún ejercicio): TMB x 1.2 - Ligera actividad (ejercicio ligero o práctica deportiva 1-3 días a la semana): TMB x 1.375 - Moderada actividad (ejercicio moderado o práctica deportiva 3-5 días a la semana): TMB x 1.55 - Alta actividad (ejercicio intenso o práctica deportiva 6-7 días a la semana): TMB x 1.725 - Muy alta actividad (ejercicio muy intenso o trabajo físico): TMB x 1.9 Recuerda, cada persona es única y debe elegir lo que mejor se adapte a su estilo de vida, hoy te cuento algunas estrategias que puedes considerar para lograr la pérdida de grasa deseada. Suscríbete al canal ¡y no te pierdas un nuevo episodio todos los lunes! ¿De qué te gustaría que hablemos en los próximos episodios? Cuéntame en los comentarios. ¡Nos vemos pronto! Contacto Laboral: info@saschafitness.com Nos leemos en mis redes sociales: Website saschafitness.com Instagram instagram.com/saschafitness Youtube youtube.com/@SaschaFitnessTV?si=GmFzFqVwkVAWL3_l Facebook facebook.com/saschafitnessoficial/?fref=ts Twitter twitter.com/saschafitness

"We come to it at last, the great podcast of our time." - Gandalf, sort of Intrepid hosts Lindy and Meagan battle common dismissals of the fantasy genre and tell us what they love and don't love about the beloved series The Lord Of The Rings. And speaking of beloved, would you marry Gimli or Aragorn? Kill Frodo or Pippin? The hosts play the most epic game of Eff Marry Kill you've ever heard with the heroes from the Fellowship Of The Ring. And finally - Lindy and Meagan make TMB history with their very first guest ever. May this episode be a light to you in dark places, when all other lights go out.  Send us your accolades! Text B-F-F to 206-926-9955 to join the Text Me Back Text Club, or email us at textmeback@kuow.org   See omnystudio.com/listener for privacy information.

Amy welcomes Ericka Young, the CEO of Tailor-Made Budgets, to the Including You podcast to discuss financial wellness. TMB provides Financial Wellness Education as an employee benefit for small- to midsize organizations. Connect with Ericka on LinkedIn. https://bit.ly/3tFIs3I Check out Ericka's website. https://bit.ly/46Pj4qM Including You is brought to you by Lead at Any Level. Learn more about them on their website. http://bit.ly/2lPvOMM Learn more about Pfizer on their website. https://bit.ly/2TTtZiZ Listen to Pfizer's "Science Will Win" podcast. https://bit.ly/3u3uoxW

Where do oral medicine specialists fit in the world of oral surgery? Here on the Everyday Oral Surgery Podcast is the oral medicine specialist, Dr. Hayley Vatcher to answer this question! Tuning in, you'll hear all about Hayley's career, the process of becoming an oral medicine specialist, the types of patients she gets, what treatment she offers, how she treats TMB, all about autoimmune conditions she sees and how she treats them, and so much more! We even delve into some interesting topics such as the emotional factors involved in oral conditions and how diet plays a role in health conditions. Finally, our guest answers our rapid-fire questions. You don't want to miss this one so press play now!Key Points From This Episode:A warm introduction to today's guest, Dr. Hayley Vatcher. Hayley tells us about what led her to oral medicine and what her practice setup is like now. Where she fits into oral surgery as an oral medicine specialist. The types of patients Hayley gets and the treatments she offers. The different ways Hayley treats TMB and the main contributing factor that may cause it. The emotional factors in oral medicine and why Haley uses animal-assisted therapy. Autoimmune conditions she sees (like Sjogren's syndrome) and how she treats them. How much diet plays a role in autoimmune conditions and other medical conditions.Hayley talks about the process of becoming an oral medicine specialist. Hayley shares the best book she's read this year. Why exercise is so beneficial for Haley's oral medicine career. Hayley shares her favorite movies and TV series and her favorite quote.Links Mentioned in Today's Episode:Dr. Hayley Vatcher Email Address — hvatcher@gmail.comDr. Hayley Vatcher on LinkedIn — https://www.linkedin.com/in/hvatcher/Charleston Oral and Facial Surgery — https://www.charlestonoralandfacialsurgery.com/KLS Martin — https://www.klsmartin.com/The Plant Paradox — https://www.amazon.com/Plant-Paradox-Dangers-Healthy-Disease/dp/006242713X/Oral and Maxillofacial Pathology — https://www.amazon.com/Oral-Maxillofacial-Pathology-Brad-Neville/dp/0323789811/refEveryday Oral Surgery Website — https://www.everydayoralsurgery.com/ Everyday Oral Surgery on Instagram — https://www.instagram.com/everydayoralsurgery/ Everyday Oral Surgery on Facebook — https://www.facebook.com/EverydayOralSurgery/Dr. Grant Stucki Email — grantstucki@gmail.comDr. Grant Stucki Phone — 720-441-6059

The Sons start the show by recapping the first few weeks of fall camp, including a look at what they know, and what they don't know so far. This sparked a UCF Mike Top 5 list of things UCF fans lie about, which sprung into conversations about the cows, Lubbock, Soccer, and OAKAAK. However, the biggest lie, according to Mike, is that fans will be good with a 6 win season. Buckle up for this one. The Sons then spin the random wheel to pick their defensive team from the current UCF players. In particular, the Sons have a hard time understanding the secondary and who will be a key player this season. Also, TMB and Josh Celiscar, who needs a bigger season? cow of the week talks Grothe and swamp ass, which are really the same thing when you think about it. Learn more about your ad choices. Visit megaphone.fm/adchoices